Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease

Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease

Ottar Nygård, M.D., Jan Erik Nordrehaug, M.D., Helga Refsum, M.D., Per Magne Ueland, M.D., Mikael Farstad, M.D., and Stein Emil Vollset, M.D., Dr.P.H.

N Engl J Med 1997; 337:230-237July 24, 1997DOI: 10.1056/NEJM199707243370403

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Abstract
Article
References
Citing Articles (677)
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BACKGROUND

Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined.

Full Text of Background…

METHODS

We prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically.

Full Text of Methods…

RESULTS

After a median follow-up of 4.6 years, 64 patients (10.9 percent) had died. We found a strong, graded relation between plasma homocysteine levels and overall mortality. After four years, 3.8 percent of patients with homocysteine levels below 9 μmol per liter had died, as compared with 24.7 percent of those with homocysteine levels of 15 μmol per liter or higher. Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infarction, the left ventricular ejection fraction, and the serum creatinine level. The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders. In an analysis in which the patients with homocysteine levels below 9 μmol per liter were used as the reference group, the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 μmol per liter, 2.8 for those with levels of 15.0 to 19.9 μmol per liter, and 4.5 for those with levels of 20.0 μmol per liter or higher (P for trend = 0.02). When death due to cardiovascular disease (which occurred in 50 patients) was used as the end point in the analysis, the relation between homocysteine levels and mortality was slightly strengthened.

Full Text of Results…

CONCLUSIONS

Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease.

Full Text of Discussion…

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FIGURE 1    
Estimated Survival among Patients with Coronary Artery Disease, According to Plasma Total Homocysteine Levels.
FIGURE 2Dose–Response Relation between Plasma Total Homocysteine Levels and Mortality.

 

 

 

 

 

Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action.

Properties of food folates determined by stability and susceptibility to intestinal pteroylpolyglutamate hydrolase action.

Seyoum ESelhub J.

J.Nutr 128:1956-1960 (1998)

Abstract

The intestinal absorption of folate occurs at the monoglutamyl level, and an important measure of food folate bioavailability is how much folate from the food reaches the intestinal sites in forms that can readily be absorbed. In the absence of protecting agents, e.g., vitamin C and reduced thiols, many labile folates may be lost during cooking and during residence in the acid-peptic milieu of the stomach. On the other hand, the presence of polyglutamyl folate necessitates the action of intestinal hydrolases, which could be affected by food constituents. In this study, we developed an in vitro assay for the determination of an index of food folate availability. The index of folate availability in this study was defined as that proportion of folate that has been identified as monoglutamyl derivatives after tests for stability and susceptibility to an enzymatic hydrolysis. The index of folate availability varied widely among foods. The highest index was for egg yolk (72.2%), followed by cow’s livers (55.7%), orange juice (21. 3%), cabbage (6.0%), lima beans (4.5%) and lettuce (2.9%). Yeast folate had the lowest index (0.3%). The availability indices generated by this study correlate with the indices of the bioavailability of the corresponding food folate observed in earlier studies, R2 = 0.529 (P = 0.068). Additional information is required on the bioavailability of other food products to test the usefulness of this in vitro approach for assessing food folate availability.

LA METHYLATION

La méthylation est l’attache ou la substitution d’un groupement méthyle ( CH3 ) sur une autre molécule. La déméthylation est au contraire, la suppression d’un groupe méthyle sur un substrat.

La valeur normale optimale  de l’homocystéine est +/- 7 micromol

Les réactions de méthylation sont des réactions biochimiques très importantes intervenant dans de nombreux processus biologiques .

Par exemple

  • la synthèse de la L-carnitine
  • synthèse de la créatine
  • Développement du tube neural de l’embryon
  • Processus de certains cancers
  • Détoxication des oestrogènes
  • Dans le cerveau , synthèse de la phosphatidyl-choline
  • Synthèse de la mélatonine (transformation de la sérotonine en mélatonine

Le déroulement de ces processus dépend d’un environnement nutritionnel correct.

L’altération de la méthylation peut entraîner :

  • cancers
  • spina bifiida
  • Dépression
  • Maladies Cardiovasculaires
  • Faiblesse musculaire
  • Fatigue
  • Fonction cognitives

 

La méthylation est un processus biochimique qui débute avec la méthionine. Ce substrat réagit avec l’ATP, et donne la SAMe (S-Adenosyl Méthionine). La SAMe contient des groupements méthyles nécessaires à la méthylation. Ces groupes CH3 se détachent du SAMe pour catalyser d’autres réactions. Le produit restant se transforme finalement en homocystéine, qui peut être toxique si non convertie. Les vitamines du groupe B , sont nécessaires à la conversion de l’homocystéine.

L’homocystéine peut également être convertie en bétaïne, un produit de la choline.

  

 

 

 

La METHYLATION est sous le contrôle de

Acide Folique

Vitatamine B12

Bétaïne

 

SAM ET   SYNTHESE DE L-CARNITINE

L-CARNITINE 

Abstract

Résumé

Objectif. – L’objectif de cette publication est de préciser l’implication de la carnitine dans le fonctionnement normal de la cellule musculaire et d’évaluer l’intérêt que pourrait représenter pour les performances physiques une supplémentation en carnitine.

Actualités. – Récemment, de nouvelles informations concernant la voie de la biosynthèse de la carnitine ainsi que de son transport dans les cellules musculaires ont été publiées. Les bases moléculaires des déficiences en carnitine ont notamment été identifiées permettant ainsi de mieux comprendre les mécanismes contrôlant l’utilisation de la carnitine dans ces cellules. Une analyse aussi exhaustive que possible a été menée afin de rechercher les conséquences, sur le fonctionnement du muscle, d’un déséquilibre de l’homéostasie de la carnitine. L’ensemble des données actuellement disponibles montre que l’absence de carnitine dans le muscle conduit à un dysfonctionnement majeur de ce tissu avec pour conséquence principale une dégénérescence musculaire souvent associée à des troubles nerveux. À l’inverse, les effets d’une supplémentation en carnitine sur le muscle et sur les capacités physiques semblent limités.

Perspectives. – En conclusion, la carnitine est rigoureusement indispensable à la survie de l’organisme mais tout apport supplémentaire n’induit pratiquement aucun bénéfice aux personnes la consommant.

Abstract

Aim. – The goal of this study was to clarify the precise role of carnitine in the normal function of muscle cell and to determine the rational for carnitine suplementation in improving physical performance.

Recent data. – Recently, new data have been reported concerning the biosynthetic pathway for carnitine as well as its intracellular transport across plasmic membranes. Molecular basis for carnitine deficiency has also been described allowing a better understanding of biochemical mechanisms involved in carnitine utilization by muscle cell. A exhaustive analysis has been conducted to determine the role of carnitine in muscle physiology. Taken together, the available data show that a carnitine deficiency in muscle cell is responsible of a major dysfunction in this tissue characterized by a myopathy usually associated with neurological disorders. On the other hand, supplementation of healthy people does not improve their athletic performances and does not markedly change biochemical muscle parameters.

Perspectives. – In conclusion, carnitine is an essential element in the oxidative pathway and its absence causes serious muscle disorders but supplementation has no major effect on muscle function.

 

ORIGINAL ARTICLE

Plasma Homocysteine Levels and Mortality in Patients with Coronary Artery Disease

Ottar Nygård, M.D., Jan Erik Nordrehaug, M.D., Helga Refsum, M.D., Per Magne Ueland, M.D., Mikael Farstad, M.D., and Stein Emil Vollset, M.D., Dr.P.H.

N Engl J Med 1997; 337:230-237July 24, 1997DOI: 10.1056/NEJM199707243370403

Share:
Abstract
Article
References
Citing Articles (677)
Letters

BACKGROUND

Elevated plasma homocysteine levels are a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined.

Full Text of Background…

METHODS

We prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically.

Full Text of Methods…

RESULTS

After a median follow-up of 4.6 years, 64 patients (10.9 percent) had died. We found a strong, graded relation between plasma homocysteine levels and overall mortality. After four years, 3.8 percent of patients with homocysteine levels below 9 μmol per liter had died, as compared with 24.7 percent of those with homocysteine levels of 15 μmol per liter or higher. Homocysteine levels were only weakly related to the extent of coronary artery disease but were strongly related to the history with respect to myocardial infarction, the left ventricular ejection fraction, and the serum creatinine level. The relation of homocysteine levels to mortality remained strong after adjustment for these and other potential confounders. In an analysis in which the patients with homocysteine levels below 9 μmol per liter were used as the reference group, the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 μmol per liter, 2.8 for those with levels of 15.0 to 19.9 μmol per liter, and 4.5 for those with levels of 20.0 μmol per liter or higher (P for trend = 0.02). When death due to cardiovascular disease (which occurred in 50 patients) was used as the end point in the analysis, the relation between homocysteine levels and mortality was slightly strengthened.

Full Text of Results…

CONCLUSIONS

Plasma total homocysteine levels are a strong predictor of mortality in patients with angiographically confirmed coronary artery disease.

Full Text of Discussion…

Read the Full Article…

MEDIA IN THIS ARTICLE

FIGURE 1    
Estimated Survival among Patients with Coronary Artery Disease, According to Plasma Total Homocysteine Levels.
FIGURE 2Dose–Response Relation between Plasma Total Homocysteine Levels and Mortality.

 

 

 

 

 

Coenzyme Q10 and Neurological Diseases

Coenzyme Q10 and Neurological Diseases

Pharmaceuticals 2009, 2, 134-149; doi:10.3390/ph203134
pharmaceuticals
ISSN 1424-8247
www.mdpi.com/journal/pharmaceuticals
Review

Michelangelo Mancuso *, Daniele Orsucci, Valeria Calsolaro, Anna Choub and Gabriele
Siciliano
Department of Neuroscience, Neurological Clinic, University of Pisa, Tuscany, Italy
* Author to whom correspondence should be addressed; E-Mail: mmancuso@inwind.it;
Tel.: +39-050-992440; Fax: +39-050-554808.
Received: 29 September 2009; in revised form: 26 November 2009 / Accepted: 30 November 2009 /
Published: 1 December 2009
Abstract: Coenzyme Q10 (CoQ10, or ubiquinone) is a small electron carrier of the
mitochondrial respiratory chain with antioxidant properties. CoQ10 supplementation has
been widely used for mitochondrial disorders. The rationale for using CoQ10 is very
powerful when this compound is primary decreased because of defective synthesis.
Primary CoQ10 deficiency is a treatable condition, so heightened “clinical awareness”
about this diagnosis is essential. CoQ10 and its analogue, idebenone, have also been
widely used in the treatment of other neurodegenerative disorders. These compounds could
potentially play a therapeutic role in Parkinson’s disease, Huntington’s disease,
amyotrophic lateral sclerosis, Friedreich’s ataxia, and other conditions which have been
linked to mitochondrial dysfunction. This article reviews the physiological roles of CoQ10,
as well as the rationale and the role in clinical practice of CoQ10 supplementation in
different neurological diseases, from primary CoQ10 deficiency to neurodegenerative
disorders.
Keywords: coenzyme Q10; idebenone; mitochondria; mitochondrial diseases;
neurodegeneration
Introduction
Coenzyme Q10 (CoQ10), or ubiquinone, is an endogenously synthesized lipid (Figure 1).
Intracellular synthesis, which depends on the mevalonate pathway, is the major source of CoQ10
OPEN ACCESS
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(Figure 2). The mevalonate pathway is a sequence of cellular reactions leading to farnesyl
pyrophosphate, the common substrate for the synthesis of cholesterol, dolichol, dolichyl phosphate,
CoQ10, and for protein prenylation (a post-translational modification necessary for the targeting and
function of many proteins) [1]. Cells synthesize CoQ10 de novo, starting with synthesis of the
parahydroxybenzoate ring and the polyisoprenyl tail, which anchors CoQ10 to membranes [1]. The
length of this tail varies among different organisms. In humans, the side chain is comprised of ten
isoprenyls producing CoQ10 [1] (see Figure 1).
Figure 1. Structure of Coenzyme Q10. Me, methyl groups.
In normal subjects, oral administration of CoQ10 improved subjective fatigue sensation and
physical performance during fatigue-inducing workload trials [2]. CoQ10 has been widely used for the
treatment of mitochondrial disorders (MD) and other neurodegenerative disorders, as well as its
analogue idebenone, which shares an identical modified parahydroxybenzoate ring with CoQ10, but
has a short 10-carbon tail. Other potential treatment indications for the use of CoQ10 include migraine
[3,4], chronic tinnitus [5], hypertension [6], heart failure and atherosclerosis [7]; however, the role of
CoQ10 in such conditions is still an open question. CoQ10, which may ameliorate endothelial
function, may be an independent predictor of mortality in chronic heart failure, and there is a rationale
for controlled intervention studies with CoQ10 in such condition [8]. Although CoQ10 is also used for
the prevention and treatment of cancer, there are no convincing evidences of efficacy [7].
No absolute contraindications are known for CoQ10, and adverse effects are rare [7]. Mild
gastrointestinal discomfort is reported in <1% of patients [7]. CoQ10 has an excellent safety record.
Important pharmacokinetic factors are non-linear absorption and enterohepatic recirculation [9].
Because of its hydrophobicity and large molecular weight, absorption of dietary CoQ10 is slow and
limited [10]. In the case of dietary supplements, solubilized CoQ10 formulations show enhanced
bioavailability. The T(max) is around 6 h, with an elimination half-life of about 33 hours [10]. The
reference intervals for plasma CoQ10 range from 0.40 to 1.91 μmol/L in healthy adults [10]. With
CoQ10 supplements there is reasonable correlation between increase in plasma CoQ10 and ingested
dose up to a certain point. Animal data show that CoQ10 in large doses is taken up by all tissues
Pharmaceuticals 2009, 2
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including heart and brain mitochondria [10]. This has implications for therapeutic applications in
human diseases. Its various formulations demonstrate variation in bioavailability and dosage
consistency, and therefore it is important to use brands that have passed independent testing for
product purity and consistency [7]. During CoQ10 supplementation plasma CoQ10 levels should be
monitored to ensure efficacy, given that there is variable bioavailability between commercial
formulations, and known inter-individual variation in CoQ10 absorption [7]. However, plasma levels
may not reflect that of the cell and other surrogates such as blood mononuclear cells may be more
appropriate [11]. Future CoQ10 research should consider uptake and distribution factors to determine
cost-benefit relationships [9].
Figure 2. A schematic representation of Coenzyme Q10 biosynthesis. The sequence of
cellular reactions that leads to farnesyl-PP is the mevalonate pathway. Farnesyl-PP is the
common substrate for the synthesis of cholesterol, dolichol, and Coenzyme Q10, as well as
for prenylation of proteins. Coenzyme Q10 contains also a benzoate ring originating from
tyrosine. 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or
statins, block production of mevalonate, a critical intermediary in the cholesterol synthesis
pathway. A hypothesized mechanism of statin myopathy involve mitochondrial
dysfunction caused by reduced intramuscular coenzyme Q10. After 4-OH-benzoate and
decaprenyl-PP are produced, at least seven enzymes (encoded by COQ2-8 genes) catalyze
condensation, methylation, decarboxylation, and hydroxylation reactions needed to
synthesize Coenzyme Q10. Abnormalities in any part of this metabolic cascade will cause
primary CoQ10 deficiency. PP, pyrophosphate.
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CoQ10 shuttles electrons from complexes I and II and from the oxidation of fatty acids and
branched-chain aminoacids (via flavin-linked dehydrogenases) to complex III of the mitochondrial
electron transport chain, ETC [1]. Reduced CoQ10 has also antioxidant properties, and therefore may
protect membrane lipids, proteins and mitochondrial DNA (mtDNA) against oxidative damage [1].
Mitochondria are dynamic and pleomorphic organelles, which evolved from the aerobic bacteria
which about 1.5 billion years ago populated primordial eukaryotic cells, thus endowing the host cells
with oxidative metabolism (much more efficient than anaerobic glycolysis) [12]. Mitochondria are
composed of a smooth outer membrane surrounding an inner membrane of significantly larger surface
area that, in turn, surrounds a protein-rich core, the matrix [12]. They contain two to ten molecules of
mtDNA [12]. In humans, the mtDNA is transmitted through maternal lineage [12]. The most crucial
task of the mitochondrion is the generation of energy as adenosine triphosphate (ATP), by means of
the ETC. The ETC is needed for oxidative phosphorylation (which provides the cell with the most
efficient energetic outcome in terms of ATP production), and consists of four multimeric protein
complexes located in the inner mitochondrial membrane [12]. The ETC also requires cytochrome c
(cyt c) and CoQ10. Electrons are transported along the complexes to molecular oxygen (O2), finally
producing water [12]. At the same time, protons are pumped across the mitochondrial inner
membrane, from the matrix to the intermembrane space, by complexes I, III, and IV. This process
creates an electrochemical proton gradient. ATP is produced by the influx of protons back through the
complex V, or ATP synthase (the “rotary motor”) [12]. This metabolic pathway is under control of
both nuclear (nDNA) and mitochondrial genomes [12]. The human mtDNA encodes information for
mitochondrial transfer RNAs (tRNAs), for ribosomal RNAs (rRNAs), and for 13 subunits of the ETC
[12]. The rest of the mitochondrial proteins are encoded by genes in the nuclear chromosomes, and
finally imported into the mitochondrion [12].
Mitochondria also play a central role in apoptotic cell death [13], and mitochondrial dysfunction
has been implicated in the pathogenesis of several neurodegenerative diseases, such as amyotrophic
lateral sclerosis (ALS), Azheimer’s (AD) and Parkinson’s disease (PD) [13]. Oxidative stress is an
earlier event associated with mitochondrial dysfunction [13]. The transport of high-energy electrons
through the mitochondrial ETC is a necessary step for ATP production, but it is also source of reactive
oxygen species (ROS) production. The sites for ROS production in mitochondrial ETC are normally
ascribed to the activity of complexes I and III [13]. On the other hand, the ETC is not universally
accepted as the major site for mitochondrial ROS generation. Other mitochondrial components, such
as monoamine oxidases and p66(Shc), might contribute to ROS generation [14].
The accumulation of ROS can potentially damage bio-molecules, including lipids, proteins and
nucleic acids [13]. The accumulation of nDNA and mtDNA oxidative damage is thought to be
deleterious in post-mitotic cells such as neurons, where DNA cannot be replaced through a cellular
division mechanism [13]. Indeed, oxidative base modifications to mtDNA could potentially cause
bioenergetic dysfunctions resulting in cell death [13]. The cells possess an intricate network of defense
mechanisms (mitochondrial manganese superoxide dismutase, glutathione peroxidase and other
molecules) to neutralize excessive accumulation of ROS and, under physiological conditions, are able
to cope with the flux of ROS [13]. Oxidative stress describes a condition in which cellular antioxidant
defences are insufficient to keep the levels of ROS below a toxic threshold [13].
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The mtDNA is particularly sensitive to oxidative damage because of its proximity to the inner
mitochondrial membrane, where oxidants are formed, and because it is not protected by histones and is
inefficiently repaired [13]. Because several of the mtDNA genes encode for subunits of the
mitochondrial ETC, oxidative mtDNA damage, if not correctly repaired, could result in mutations and
deletions disrupting the function of genes involved in the production of ATP, ultimately leading to
mitochondrial dysfunction, increased production of ROS, and cellular death [13].
Several studies investigated the role of CoQ10 as a neuroprotective agent versus ROS damage and
apoptotic cell death. CoQ10 may act by stabilizing the mitochondrial membrane when neuronal cells
are subjected to oxidative stress [15]. Pre-treatment with water-soluble CoQ10 maintained
mitochondrial membrane potential during oxidative stress and reduced the amount of mitochondrial
ROS generation [15]. The evidence of mitochondrial involvement in neurodegenerative diseases
allowed the hypothesis that CoQ10 may have a protective role in such diseases [13].
For instance, increasing evidence suggests that AD is associated with oxidative damage and
mitochondrial dysfunction [13,16]. Exogenous CoQ10 was found to protect neuroblastoma cells from
β-amyloid neurotoxic effect; dietary supplementation of CoQ10 to AD mice suppressed brain protein
carbonyl levels, which are markers of oxidative damage [13]. This suggests that oral CoQ10 may be a
viable antioxidant strategy for neurodegenerative disease [16]. The efficacy of CoQ10 treatment
against β-amyloid induced mitochondrial dysfunction has been evaluated also in brains of diabetic rats,
where CoQ10 treatment was found to attenuate the decrease in oxidative phosphorylation and avoided
the increase in hydrogen peroxide production induced by the neurotoxic peptide [17]. An in vivo
volume MRI study on mice with mutation in the amyloid precursor protein showed that CoQ10
significantly delayed hemispheric and hippocampal atrophy [18]. Furthermore, the efficacy of CoQ10
as a neuroprotective factor against cognitive impairment has been evaluated in mice with reduced
cognitive performance [19]. In aged mice CoQ10, combined with alpha-tocopherol, could have a role
in improving learning [20].
Moreover, the antioxidant function of CoQ10 has been also studied in noise-induced hearing loss
(NIHL). The mitochondrial ETC is source of ROS also in NIHL, and anti-oxidants and free-radicals
scavengers have been shown to attenuate the damage [21]. The therapeutic application of CoQ10 is
limited by the lack of solubility and poor bioavailability, therefore it is a challenge to improve its water
solubility in order to ameliorate the efficacy in tissues and fluids [21]. Fetoni and co-workers [21]
reported that the administration of a water-soluble CoQ10 formulation to a guinea pig model of
acoustic trauma resulted to prevent apoptosis and improved hearing. The effectiveness of CoQ10 was
compared with a soluble formulation of CoQ10 (multicomposite CoQ10 Terclatrate, Q-ter) [21].
Functional and morphological studies were carried out, and animals injected with Q-ter showed a
greater degree of activity in preventing apoptosis and in improving hearing [21]. These data confirm
that solubility of CoQ10 may improve its ability in preventing oxidative stress and apoptosis resulting
from mitochondrial dysfunction.
Coenzyme Q10 and Neurodegeneration
There is increasing evidence that impairment of mitochondrial function and oxidative damage are
contributing factors to the pathophysiology of Parkinson’s Disease (PD). Complex I dysfunction has
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been implicated in the pathogenesis of PD [13]. A recent study reported a deficit in brain CoQ10 levels
in PD patients, which may be involved in the pathophysiology of PD [22]. Winkler-Stuck and coworkers
[23] observed that the activity of ETC complexes, which were impaired in skin fibroblasts
from a subgroup of PD patients, was restored after cultivation in the presence of 5 μM CoQ10. The
neuroprotective role of CoQ10 has been also studied in other cellular models of PD, such as ironinduced
apoptosis in cultured human dopaminergic neurons [24]. Iron-induced damage is mediated by
ROS production and apoptosis activation; CoQ10 attenuated such iron-induced cellular damage [24].
CoQ10 has been also found to be effective in a PD mouse model of MPTP toxicity, reversing
dopamine depletion, loss of tyrosine hydroxylase neurons and induction of alpha-synuclein inclusions
in the substantia nigra pars compacta [23]. In PD patients, CoQ10 was well tolerated at doses as high
as 1,200 mg daily (a mild effect of CoQ10 1,200 mg/day on UPDRS score has been also reported in
this study) [25]. A study on 130 PD patients without motor fluctuations and a stable antiparkinsonian
treatment reported that nanoparticular CoQ10 (300 mg daily) was safe and well tolerated, and led to
plasma levels similar to 1,200 mg/day of standard formulations, although did not result in symptomatic
effects in midstage PD [26]. The efficacy of CoQ10 in PD remains an open question [27]. A very
recent short-term, randomized, placebo-controlled trial was performed in progressive supranuclear
palsy (PSP). PSP, the second most common cause of parkinsonism after PD, is characterized by down
gaze palsy with progressive rigidity and imbalance leading to falls. Impairment of mitochondrial ETC
complex I activity has been reported in PSP [28]. CoQ10 improved cerebral energy metabolism on
magnetic resonance spectroscopy studies [28]. Clinically, PSP patients improved slightly, but
statistically significantly, upon CoQ10 treatment compared to placebo [28].
Huntington’s Disease (HD) is a genetic disease characterized by psychiatric disturbances,
progressive cognitive impairment, choreiform movements, and death 15 to 20 years after the onset of
symptoms. Various lines of evidence demonstrated the involvement of mitochondrial dysfunction in
the pathogenesis of HD, but the precise role of mitochondria in the neurodegenerative cascade leading
to HD is still unclear. In a mouse model of HD in vivo phosphorus magnetic resonance spectroscopy
(31P-MRS) has been used in order to evaluate the antioxidant effect of CoQ10 and vitamin E on the
activity of creatine kinase (CK), a sensitive indicator of brain energy metabolism dysfunction [29]. The
results showed that CoQ10 and vitamin E prevented the increase of CK and the decrease of CoQ10
content in brain tissue, but were ineffective to prevent the decline of ETC function [29]. Smith and coworkers
[30] reported that CoQ10 administration resulted to exert a therapeutic benefit in a dose
dependent manner in HD mice, improving motor performance and grip strength, and reducing weight
loss, brain atrophy and huntingtin inclusions [30]. Combined minocycline (an antibiotic with antiapoptotic
and neuroprotective properties) and CoQ10 therapy in a mouse model of HD ameliorated
behavioral and neuropathological alterations, reduced gross brain atrophy, striatal neuron atrophy, and
huntingtin aggregation, and significantly extended survival and improved motor performance to a
greater degree than either minocycline or CoQ10 alone [31]. In HD patients, CoQ10 may slow the
decline in total functional capacity over 30 months [32]. Kieburtz and co-workers [32] carried out a
trial in which 347 patients with early HD were randomized to receive CoQ10 300 mg twice daily,
remacemide hydrochloride 200 mg three times daily, both, or neither treatment, and were followed
every 4 to 5 months for a total of 30 months. Patients treated with CoQ10 showed a trend toward
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slowing the decline in total functional capacity decline over 30 months, as well as beneficial trends in
some secondary measures [32]. CoQ10 was well tolerated by HD patients.
Moreover, CoQ10 resulted to be safe in 31 subjects with Amyotrophic Lateral Sclerosis (ALS)
treated with doses as high as 3,000 mg/day for 8 months [33]. ALS is a devastating disease, with
selective degeneration of the anterior horn cells of the spinal cord and cortical motor neurons. The
aetiology and pathogenesis of the sporadic form of the disease are poorly understood, but
mitochondrial dysfunction and oxidative stress are probably involved [13]. A significant increase in
the oxidized form of CoQ10 and in the ratio of oxidized form of CoQ10 to total CoQ10 have been
reported in 20 sporadic ALS patients [34]. Moreover, the latter parameter significantly correlated with
the duration of disease, supporting systemic oxidative stress in the pathogenesis of sporadic ALS [34].
Very recently, in order to choose between two high doses of CoQ10 for ALS and to determine if it
merits testing in a Phase III clinical trial, Kaufmann and co-workers [35] performed a multicenter trial
on 185 patients. There were no safety concerns, but this study showed no significant differences
between CoQ10 at 2,700 mg/day for 9 months and placebo [35].
Most trials have demonstrated that idebenone (5 mg/kg daily) reduced cardiac hypertrophy in
Friedreich’s ataxia [36]. Friedreich’s ataxia is the most common hereditary ataxia among white
people, and it is caused by a trinucleotide expansion in the X25 gene. In this disorder, the genetic
abnormality results in the deficiency of frataxin, a protein targeted to the mitochondrion [36].
Although the exact physiological function of frataxin is not known, its involvement in iron–sulphur
cluster biogenesis has been suggested. A possible manifestation of this disease is cardiomyopathy. A
pilot study investigated the potential for high dose CoQ10/vitamin E therapy to modify clinical
progression in Friedreich’s ataxia [37]. Fifty patients were randomly divided into high or low dose
CoQ10/vitamin E groups [37]. At baseline serum CoQ10 and vitamin E levels were significantly
decreased in patients [37]. During the trial CoQ10 and vitamin E levels significantly increased in both
groups [37]. Serum CoQ10 level resulted to be the best predictor of a positive clinical response to
CoQ10/vitamin E therapy [37]. Recently, a randomised, placebo-controlled trial has been conducted
on 48 patients with genetically confirmed Friedreich’s ataxia [38]. Treatment with higher doses of
idebenone was generally well tolerated and associated with improvement also in neurological function
and activities of daily living in patients with Friedreich’s ataxia [38]. The degree of improvement
correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a
beneficial effect on neurological function [38].
The role of mitochondrial dysfunction and oxidative stress in the pathogenesis of neurodegenerative
diseases is well documented [13]. It will be important to develop a better understanding of the role of
oxidative stress and mitochondrial energy metabolism in neurodegeneration, since it may lead to the
development of more effective treatment strategies for these devastating disorders.
Coenzyme Q10 Deficiency and Other Mitochondrial Disorders
There is a strong rationale for using CoQ10 supplementation to treat patients with CoQ10
deficiency [39]. CoQ10 deficiency is a rare, autosomal recessive, heterogeneous condition which has
been associated with five major syndromes: (i) encephalomyopathy (with recurrent myoglobinuria,
brain involvement and ragged red fibers); (ii) severe infantile multisystemic disease; (iii) cerebellar
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ataxia; (iv) Leigh syndrome (growth retardation, ataxia and deafness); (v) isolated myopathy [39].
Primary CoQ10 deficiencies due to mutations in ubiquinone biosynthetic genes (i.e., COQ2, PDSS1,
PDSS2, CABC1) have been identified in patients with the infantile multisystemic and cerebellar ataxic
phenotypes [40]. In contrast, secondary CoQ10 deficiencies, due to mutations in genes not directly
related to ubiquinone biosynthesis (i.e., APTX, ETFDH, BRAF) [40], have been identified in patients
with cerebellar ataxia, pure myopathy, and cardiofaciocutaneous syndrome [40].
The myopathic form of CoQ10 deficiency is a rare disease characterized by subacute (3–6 months)
onset of exercise intolerance and proximal limb weakness without central nervous system
involvement, increased serum lactate and CK levels. Frequently it is associated with lipid droplets
with subtle signs of mitochondrial dysfunction at skeletal muscle level, and reduced complexes I + III
and II + III activities (because CoQ10 shuttles electrons from complexes I and II to complex III of the
mitochondrial ETC), and good clinical response to CoQ10 supplementation [39]. Therefore, a correct
and timely diagnosis is crucial. The myopathic form of CoQ10 deficiency has been associated to
mutations in the electron-transferring-flavoprotein dehydrogenase (ETFDH) gene [41]. ETFDH is also
linked to another metabolic disorder, glutaric aciduria type II (GAII) [41]. Myopathic CoQ10
deficiency with pathogenic ETFDH mutations and late-onset GAII probably are the same disease [41].
As CoQ10 is the direct acceptor of electrons from the electron-transferring-flavoprotein, the lack of
the reducing enzyme may downregulate the synthesis of CoQ10 [41]. Alternatively, faulty binding of
the enzyme to CoQ10 could result in excessive degradation of the acceptor molecule [41]. Since
CoQ10 deficiency/late-onset GAII is treatable, the diagnosis should be considered both in children
and in adults with high-serum CK, proximal myopathy (with or without hepatopathy or
encephalopathy), multiple acyl-CoA deficiency, lipid storage myopathy and decreased activity of ETC
complexes I and II + III (and IV) [41]. It has been suggested that patients should be treated with both
CoQ10 and riboflavin [41].
Infantile mitochondrial encephalomyopathy has been associated to mutations in the first and second
subunits of decaprenyl diphosphate synthase (PDSS1 and PDSS2), in the mevalonate pathway [40].
Mutations in PDSS1 seem to lead to a milder phenotype than mutations in subunit 2. Patients with
mutations in para-hydroxybenzoate-polyprenyl transferase (COQ2), a component of the CoQ10
biosynthesis complex (see Figure 2) which condenses the parahydroxybenozoate ring with the
decaprenyl side-chain, share early-onset nephrosis and encephalophaty [39,40]. Very recently, a
patient with primary CoQ10 deficiency whose clinical history started with neonatal lactic acidosis and
who later developed multisystem disease including intractable seizures, global developmental delay,
hypertrophic cardiomyopathy, and renal tubular dysfunction was reported to harbour a homozygous
stop mutation affecting a highly conserved residue of COQ9 gene, leading to the truncation of 75
amino acids [42]. Interestingly, some cases of the ataxic variant of CoQ10 deficiency have been linked
to a homozygous mutation in the aprataxin (APTX) gene, which causes ataxia oculomotor apraxia type
1 [43]. The relationship beetween this protein, involved in DNA repair, and CoQ10 homeostasis is
still unclear [43]. CoQ10 deficiency with cerebellar ataxia has been associated to mutation in
CABC1/COQ8/ADCK3 gene [44,45].
CoQ10 deficiency is a treatable condition, so heightened “clinical awareness” about this diagnosis
is essential, especially for pediatricians and infantile neurologists. An early treatment with high-dose
CoQ10 might radically change the natural history of this group of diseases [39]. Patients with all
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forms of CoQ10 deficiency have shown clinical improvement with oral CoQ10 supplementation, but
cerebral symptoms are only partially ameliorated (probably because of irreversible structural brain
damage before treatment and because of poor penetration of CoQ10 across the blood-brain barrier).
Patients were given various doses of CoQ10 ranging from 90 to 2000 mg daily. The small number of
patients precluded any statistical analysis but improvement was undoubtedly reported [39]. In several
patients CoQ10 supplementation also ameliorated the mitochondrial function (ETC activities, lactic
acid values, muscle CoQ10 content). The beneficial effects of exogenous CoQ10 require high doses
and long-term administration. Also patients with ataxia oculomotor apraxia type 1 may benefit from
this treatment [39].
CoQ10 deficiencies constitute a subgroup of mitochondrial disorders (MD), a group of disorders
caused by impairment of the mitochondrial ETC [12]. The effects of mutations which affect the ETC
may be multisystemic, with involvement of visual and auditory pathways, heart, central nervous
system, and skeletal muscle [12]. The estimated prevalence of MD is 1-2 in 10000 [46]. MD are,
therefore, one of the commonest inherited neuromuscular disorders. The genetic classification of MD
distinguishes disorders due to defects in mtDNA from those due to defects in nDNA [12]. The first
ones are inherited according to the rules of mitochondrial genetics (maternal inheritance, heteroplasmy
and the threshold effect, mitotic segregation) [12]. Each cell contains multiple copies of mtDNA
(polyplasmy), which in normal individuals are identical to one another (homoplasmy) [12].
Heteroplasmy refers to the coexistence of two populations of mtDNA, normal and mutated. Mutated
mtDNA in a given tissue have to reach a minimum critical number before oxidative metabolism is
impaired severely enough to cause dysfunction (threshold effect) [12]. Differences in mutational loads
surpassing the pathogenic threshold in some tissues but not in others may contribute to the
heterogeneity of phenotypes. Because of the mitotic segregation, the mutation load can change from
one cell generation to the next and, with time, it can either surpass or fall below the pathogenic
threshold [12]. Further, the pathogenic threshold varies from tissue to tissue according to the relative
dependence of each tissue on oxidative metabolism [12]. For instance, central nervous system, skeletal
muscle, heart, endocrine glands, the retina, the renal tubule and the auditory sensory cells are highly
dependent on oxidative metabolism for energy generation. MD related to nDNA are caused by
mutations in structural components or ancillary proteins of the ETC, by defects of the membrane lipid
milieu, of CoQ10 biosynthetic genes (discussed above) and by defects in intergenomic signalling
(associated to mtDNA depletion or multiple deletions) [12]. Moreover, the occurrence of a single
large-scale deletion, common cause of progressive external ophthalmoplegia (PEO), is almost
sporadic [12].
In MD patient muscle homogenates, significantly positive correlation was observed between
complexes I + III and II + III activities with CoQ10 concentration [47]. CoQ10 levels resulted low in
some patients with MD [48]. Recently, CoQ10 content and ETC enzyme analysis were determined in
muscle biopsy specimens of 82 children with suspected mitochondrial myopathy [49]. Muscle total,
oxidized, and reduced CoQ10 concentrations were significantly decreased in the probable defect group
[49]. Total muscle CoQ10 was the best predictor of an ETC complex abnormality [49]. Determination
of muscle CoQ10 deficiency in children with suspected MD may facilitate diagnosis and encourage
earlier supplementation of this agent [49].
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Therapy of MD is still inadequate, despite great progress in the molecular understanding of these
disorders. Apart from symptomatic therapy, administration of metabolites and cofactors, including
CoQ10, as well as of ROS scavengers, is the mainstay of real-life therapy. On the other hand, there is
currently no clear evidence supporting the use of any intervention in MD [50], and further research is
needed. There have been very few randomised controlled clinical trials for the treatment of MD.
Those that have been performed were short, and involved fewer than 20 study participants with
heterogeneous phenotypes [50].
The multitude of generally positive anecdotal data [51] together with the lack of negative side
effects has contributed to the widespread use of CoQ10 in MD. In studies with eight to 44 patients
CoQ10 seemed to demonstrate positive trends in mitochondrial encephalomyopathy, lactic acidosis,
and stroke-like syndrome (MELAS), Kearns-Sayre syndrome (KSS), and myoclonus epilepsy with
ragged red fibers (MERRF) [7]. Chen and co-workers [52] performed a randomised, double-blind
cross-over trial on eight MD patients. Both subjective and objective measures showed a trend towards
improvement on treatment, but the global Medical Research Council (MRC) index score of muscular
strength was the only measure reaching statistical significance [52]. However, there is a need for
controlled trials in large cohorts of patients [50].
Recently, Rodriguez and co-workers [53] studied the effect of a combination therapy (creatine,
CoQ10, and lipoic acid) on several outcome variables using a randomized, double-blind, placebocontrolled,
crossover study design in seventeen patients with various MD. Lipoic acid is found
naturally within the mitochondria and is an essential cofactor for pyruvate dehydrogenase and α-ketoglutarate
dehydrogenase, and is also a potent antioxidant [53]. Such combination therapy resulted in
lower resting plasma lactate and a lowering of oxidative stress as reflected by a significant reduction
in urinary 8-isoprostanes and a directional trend in 8-hydroxy-2’-deoxyguanosine (8-OHdG) excretion
[53]. Isoprostanes are prostaglandin-like compounds formed by the peroxidation of arachadonic acid,
and are considered one of the most reliable markers to assess oxidative stress in vivo. 8-OHdG is
formed by the hydroxylation of guanosine residues and is often used as a biomarker of oxidative
damage to DNA. Further, the combination therapy attenuated the decrease in peak ankle dorsiflexion
strength that was observed following the placebo phase [53].
A synthetic shorter chain CoQ10 analogue is idebenone. It has been reported to improve brain and
skeletal muscle metabolism in isolated cases of MD, and seemed to enhance the rate and degree of
visual recovery in Leber Hereditary Optic Neuropathy [50].
Therapy for MD remains inadequate and mostly symptomatic, but the rapidly increasing knowledge
of their molecular defects and pathogenic mechanisms allows for some cautious optimism about the
development of effective treatments in the next future [12]. One of the “cocktails” of choice for the
treatment of MD may be a combination of L-carnitine (1,000 mg three times a day) and CoQ10 (at
least 300 mg a day), with the rationale of restoring free carnitine levels and exploiting the oxygen
radical scavenger properties of CoQ10 [12].
Statin Myopathy
Statins are currently the most effective medications for reducing low-density lipoprotein (LDL)
cholesterol concentrations [54]. Statins competitively inhibit HMG-CoA reductase thereby decreasing
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synthesis of mevalonate, a critical intermediary in the cholesterol synthesis pathway [54]. Their most
serious and frequent side effects are a variety of myopathic complaints ranging from mild myalgia to
fatal rhabdomyolysis [54]. Statins block production of farnesyl pyrophosphate, an intermediate in the
synthesis of CoQ10 [54].
The fact that statins block the mevalonate pathway has prompted the idea that statin-induced
CoQ10 deficiency may be involved in the pathogenesis of statin myopathy (the primary adverse effect
limiting their use) [54]. Therefore, supplementing with CoQ10 may be recommended to prevent the
myopathic side effects associated with the statins. Evidences for or against this hypothesis have been
reviewed by Marcoff and Thompson [54], but the question remains to be answered. A study
performed on a sample of muscle biopsy of patients with statin drug-related myopathy showed that the
decrease of CoQ10 concentration in muscle did not cause histochemical or biochemical evidence of
mitochondrial myopathy or morphologic evidence of apoptosis in most patients [55].
A study designed to assess the effect of high-dose statin treatment has been performed on 48
patients with hypercholesterolemia, randomly assigned to receive simvastatin, atorvastatin, or placebo
for 8 weeks [56]. Muscle ubiquinone concentration was reduced significantly in the simvastatin group,
but no reduction was observed in the atorvastatin or placebo group [56]. Also ETC and citrate
synthase activities were reduced in patients taking simvastatin [56].
The effect of simvastatin on CoQ10 plasmatic levels has been compared with the effect of
ezetimibe (a cholesterol absorption inhibitor) and of the coadministration simvastatin/ezetimibe [57].
While simvastatin and the combination of simvastatin and ezetimibe significantly decreased plasma
CoQ10 levels, ezetimibe monotherapy did not [57].
A randomized double-blind, placebo-controlled study that examined the effects of CoQ10 and
placebo in hypercholesterolemic patients treated by atorvastatin showed a similar decrease in LDL
carriers in the two groups and an high increase of CoQ10 levels in the CoQ10 group [58]. The placebo
group showed a mean reductions of plasma CoQ10 levels by 42%, whereas patients supplemented
with CoQ10 showed a mean increase in plasma CoQ10 by 127% [58]. However, these changes in
plasma CoQ10 levels showed no relation to the changes in serum transaminase and CK levels [58].
Further studies are needed in order to evaluate the role of CoQ10 supplementation during statin
therapy [54].
Migraine
Sandor and co-workers [3] compared CoQ10 (3 × 100 mg/day) and placebo in 42 migraine patients
in a double-blind, randomized, placebo-controlled trial. CoQ10 was superior to placebo for attackfrequency,
headache-days and days-with-nausea in the third treatment month [3]. Therefore, it has
been suggested that CoQ10 was efficacious and well tolerated.
More recently, Hershey and co-workers [4] measured CoQ10 levels in 1550 patients with paediatric
and adolescent migraine headache, and found that 32.9% were below the reference range. Patients with
low CoQ10 were recommended to start 1 to 3 mg/kg per day of CoQ10 in liquid gel capsule
formulation. In a subset of patients who returned for timely follow-up total CoQ10 levels improved (P
< 0.0001) and the headache frequency and disability seemed to reduce (P < 0.001). More rigorous
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studies are needed in order to evaluate if determination of CoQ10 levels and consequent
supplementation may result in clinical improvement in migraine patients [4].
Conclusions
The generalized mitochondrial defect might be in vitro ameliorated by CoQ10 treatment [15]. In
addition to primary CoQ10 deficiency, CoQ10 treatment may have some efficacy in the treatment of
MD and neurological disorders not directly linked to a primary deficiency in this quinone, but in
general terms linked to mitochondrial dysfunction and oxidative stress [13]. CoQ10 therapy has been
shown to be relatively safe as far as the adverse effects. Further studies on the potential usefulness of
CoQ10 supplementation in neurological diseases are strongly needed, in case also with water-soluble
formulations, which have been suggested to improve the ability of CoQ10 in preventing oxidative
stress and apoptosis resulting from mitochondrial dysfunction [21].
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DETOXICATION

DEFINITION

 

La détoxication est la transformation , par un ensemble de réactions biochimiques complexes, des substances étrangères à l’organisme ou potentiellement toxiques pour permettre leur élimination.

Sans détoxication , il y a accumulation de toxines, puis altération fonctionnelle, maladies, et mort.

PRINCIPAUX EMONCTOIRES

Système digestif

Système urinaire

Système respiratoire

Peau et muqueuses

 

IMPORTANCE DE LA PHASE D’EXCRETION

L’utilisation naturelle des émonctoires demeure la façon la plus rapide d’éliminer les toxines

Le mauvais fonctionnement d’un émonctoire risque de surcharger les autres

La surcharge de l’ensemble des émonctoires entraîne le passage à la phase de réaction

Le foie et la détoxication hépatique

La détoxication est la transformation par un ensemble de réactions biochimiques complexes,des substances étrangères à l’organisme ou potentiellement toxiques pour en permettre leur élimination

 Chimique                                                                                                    Nutritionnelle

Xénobiotiques                                                                                           Alimentation en excès

Organiques                                                                                                additifs, alcool,acides                                                    gras trans

Physiques                                                                                                  Infection

Blessure                                                                                                    endotoxines et exotoxines

Inflammation                                                                                             Bactérienne, Fungique,Virale

Exercices en excès                                                                                    Parasitaire

 

 

L’utilisation naturelle des émonctoires demeure la façon la plus simple d’éliminer les toxines.

Le mauvais fonctionnements d’un émonctoire risque de surcharger les autres.

La surcharge de l’ensemble des s entraîne le passage à la phase de réaction.

LE FOIE ET LA DETOXICATION HEPATIQUE

Expositions aux toxines

Chimique : xenobiotiques,Organiques

Physique : Blessure, inflammation, exercices physiques en excès

Nutritionnelle :  Alimentation en excès, additifs, alcool, acides gras trans

Infections : Endotoxines et exotoxines, Bactériennes, fungiques, parisitaires

LES PHASES DE DETOXICATION

PHASE I : FONCTIONALISATION

Réaction qui utilise l’oxygène pour former un site réactif . C’est l’introduction d’un groupement fonctionnel dans des molécules apolaires.

Cette fonctionalisation se fait par l’intermédiaire d’un complexe enzymatique : les cytochromes P 450

PHASE II : CONJUGAISON

La formation de conjugués

Addition d’un groupe hydrosoluble au site réactif. C’est le couplage de molécules chargées négativement et très polaires aux substrats à détoxiquer.

Entre les deux phases, des réactifs intermédiaires potentiellement toxiques et dangereux pour la cellule sont produits.Possibles lésions d’ADN , ARN , Protéines

Après la phase II , il apparaît des métabolites hydrosolubles excretables

L’équilibre entre les activités de la phase I et de la Phase II détermine la durée pendant laquelle les substances intermédiaires biotransformées persistent dans l’organisme.

CYTOCHROME P 450

La fonction principale du cytochrome P450 c’est de rajouter un groupement fonctionnel aux molécules toxiques non polaires , comme par exemple un groupe OH

C’est une famille superbe d’enzymes CypP450

La première défense enzymatique contre les composants étrangers

Au moins 10 familles connues actives dans la Phase I (plus de 150 enzymes)

Ces enzymes sont impliqués dans le métabolisme des médicaments, mais également dans la détoxication des molécules endogènes telles que les stéroïdes.

Ce sont des protéines inductibles. Nécessitent un facteur de transcription (substrat à détoxiquer.

La promiscuité de substrat. Ces enzymes peuvent détoxiquer ds molécules apparentées.

Elles font l’objet d’un polymorphisme important.

PRINCIPALES FONCTIONS CYTOCHROME P450

Catalyse de nombreuses biotransformations

  • Substrat endogènes (haute spécificité)

synthèse des stéroïdes, des acides gras, des prostaglandines

  • substrats exogènes(faible spécificité)

biotransformation des xénobiotiques, en vue d’une élimination de l’organisme (détoxification)

PRINCIPALES REACTIONS CYTOCHROME P450

  • Hydroxylations aliphatiques et aromatiques
  • N-,O- et S-désalkylations
  • Désaminations oxydatives
  • Formation de sulfoxydes
  • N-hydroxylation
  • Deshalogénation

MULTIPLICITE DES  CYTOCHROMES P450

  • Famille d’enzymes constitués de plus de 500 gènes  CYP3A4
  • Plus de 50 gènes chez l’homme, dont seuls une douzaine métabolisent les CYP2D6 médicaments CYP2C9
  • 6 isoenzymes sont responsables de la quasi-totalité des voies métaboliques P450-dépendantes CYP1A2
  • L’abondance dans le foie de chaque isoenzyme est très différente CYP2E1

QUELQUES EXEMPLES

CYP3A4   testosterone, supermuscle, PILLS

CYP3A3    peanuts, aflatoxin,vitamine B1

CYP2E1   éthanol

CYP1A2   caféine

CYP2C9    rat poison

SUBSTANCES POUVANT INDUIRE LES ENZYMES P450

acétate,                                       oranges

Alcool                                            pesticides Organophosphorés

Barbituriques                                 Vapeur de peinture

Tétrachlorure de carbone                Riboflavine

Viandes grillées                              Sassafras

Dioxines                                            Graisses saturées

Exhaust fumes                                  Hormones Stéroïdes

Diète protéinée                                  Sulfonamides

Niacin                                                 Tangerines

 

 

PHASE II: CONJUGAISON avec acide glucuronique, glycine, glutathion, ou sulfate

 

CYP3A4  (55%), CYP 2D6,(10 %) ,  et CYP2C9 (10 %) sont spécialisés dans le métabolisme de Xénobiotiques

Phase I fonctionnalisation, Phase II Conjugaison

Phase II , les groupements fonctionnels réagissent ensuite avec les molécules de conjugaison pour neutraliser les toxines et les rendre hydrosolubles

PHASE II de DETOXICATION  ou CONJUGAISON

Elle suit l’activation de la phase I mais se déroule dans le cytosol

Transforme le xénobiotique activé en composé hydrosoluble excrétable via les urines ou la bile

Les réactions nécessitent différents cofacteurs qui doivent être fournis par des sources alimentaires

REACTION DE CONJUGAISON

Couplage d’une molécule endogène (endocon: endogenous conjugating molecule) , avec un substrat qui peut être un xénobiotique ou une molécule endogène qui doit être éliminée.

Endocon ( entité chimique transférée au substrat ):

Groupe méthyle , acétyle ou autre acyles

Acide glucuronique , autres sucres

Groupe sulfate, phospate.

Glycine et d’autres acides aminés.

Diglycérides

Cholestérol et d’autres stérols

Glutathion et d’autres sulfites.

Carbonyles , Co2,S ,..

Glucurono conjugaison ou glucuronidation

Sulfatation

Formation d’acide mercapturique- conjugaison avec le glutathion

Acylation et glycino conjugaison

Conjugaison par méthylation

Type de conjugaison                         transférase                           donneur endogène

Glucuronidation                        UDP-glucuronyltransférases           Acide UDP glucuronique

Acétylation                                  N-acétyltransférase                          Acetyl CoA

Conjugaison à la glycine       Acyl-CoA glycine transférases               Glycine

Sulfatation                                 Sulfotransférases                            Phosphoadénosyl/                                                                                                                     phosphosulfate

Méthylation                                Méthyltransférases                          S-adénosyl-méthionine

Image DG_94_PICT.jpg

 polymorphisme génétique

Présence au sein de la population d’au moins 2 variants stables d’une même isoforme → capacité métaboliques différentes
 

♦ mécanisme :mutation
-substitution ou insertion de base
-délétion de base
-défaut d’épissage
ex :codon stop prématuré → Protéine tronquée inactive
→ en général ,2 phénomènes dans la population :
métaboliseurs lents (limites) :2 allèles mutés
métaboliseurs rapides (extensifs) : 1 ou 2 allèles sauvages
= distribution bimodale

nombre de sujets

métaboliseurs rapides
métaboliseurs lents

log rapport métab = substance mère/métabolite

fréquence
seuil thérapeutique
seuil toxique

concentration à l’état d’équilibre

Polymorphisme connu pour CYP :2D6 2C19 2C9 1A 2E1 (3A4 ?)

 REACTION DE PHASE II :
CONJUGAISON
RH_ R-OH _ R-OX

conjugaison avec un composé endogène
⇒formation d’un composé polaire
6 réactions :
-glucuroconjugaison
-glutathion
-acétylconjugaison
-sulfconjugaison
-méthylconjugaison
-conjugaison aux acides aminés

LES ENZYMES de la DETOXICATION PRESENTENT UN POLYMORPHISME GENETIQUE 

CYP2D6

Production de morphine à partir de la codéine: impact du statut de métaboliseur et de la quinidine

IMPACT CLINIQUE D’UNE DEFICIENCE GENETIQUE DU METABOLISME

  • Toxicité aiguë si fort premier passage hépatique
  • Accumulation toxique si métabolisme lent
  • Effets secondaires inhabituels dus à la formation augmentée de métabolites secondaires par blocage de la voie usuelle de dégradation
  • Résistance au traitement par blocage de l’activationd’un pré-médicament
  • Interactions médicamenteuses par inhibition plus marquée dose-dépendante de P450

REGULATION DE LA DETOXICATION

Régulation des activités de Détoxication

  • Les mécanismes de détoxication sont inductibles ou inhibés en fonction de la présence des différents xénobiotiques
  • Ces mécanismes de détoxication sont également influencés par :

Polymorphisme génétique

Age et sexe (sensibilité aux hormones)

Régime et mode de vie ( comme le tabagisme)

Environnement

Maladies

 

De nombreuses substances peuvent intervenir en ralentissant ou en induisant les deux phases de la détoxication hépatique.

C’est le cas de médicaments mais également de substances alimentaires naturelles.

Une expression appropriée des enzymes de phase I est indispensable pour une détoxication efficace

CYP 450 Phase I sous -expression

  • accumulation de toxines dans le tissus adipeux
  • Les taux de métabolisation des toxines sont compromis
  • Manifestation de symptômes d’intoxication

CYP-450 Phase I sur -expression

  • Formation d’intermédiaires plus réactifs qui peuvent être neutralisés par les enzymes de phase II
  • Provoque chez les patients un risque de dommages tissulaires réactifs.

INDUCTION DE LA DETOXICATION

Des inducteurs mono-fonctionnels conduisent à une augmentation de l’activité de la Phase I avec peu ou pas d’induction de la phase II

  • Les hydrocarbures polycycliques des cigarettes et les Aryl amines des viandes grillées induisent dramatiquement Cyp1A1 et Cyp1A2
  • Les glucucorticoïdes, les anti-convulsivants induisent Cyp3A4
  • L’éthanol, l’acétone induisent le Cyp2E1

Une induction des activités de la phase I sans co-induction de la phase II peut conduire à un découplage des phases I et II, avec un niveau élévé d’intermédiaires réactifs et des dommages au DNA , au RNA et aux protéines.

Les inducteurs multi-fonctionnels conduisent à une augmentation significative de plusieurs enzymes de phase II

  • C’est le cas de nombreux flavonoïdes de fruits et de légumes
  • Ellagic acid (la peau de raisin rouges) induit plusieurs enzymes de phase II et dminue l’activité de la phase I
  • Huile d’ail, soja, chou, chou de Bruxelles induisent aussi différentes enzymes de phase II

En général , une augmentation de la phase II assure une meilleure détoxication et aide à améliorer et maintenir un équilibre sain entre les phases I et phases II

 

INHIBITION DE LA DETOXICATION

Inhibition due à la compétition entre deux composés ou plus pour la même enzyme de détoxication de phase I ou II

Inhibition du à une diminution de cofacteurs indispensables à une enzyme de phase II de détoxication.

EXEMPLE D’INDUCTION OU INHIBITION PAR L’ALIMENTATION

  • Inhibiteurs du CYP3A4

Jus de pamplemousse (bergamottine)

Fruits tropicaux

  • Inducteurs du CYP1A1 , CYP1A2

Brocoli

Choux de Bruxelles

Viandes grillées

LES ALIMENTS

  • Jus de grapefruit

inhibition du CYP3A4

Autres agrumes (citron, orange…) sans effet

Augmentation des concentrations plasmatiques : antagonistes du calcium , ciclosporine, cisapride

  • Jus de grapefruit

Impact sur la pharmacocinétique de la félodipine

INACTIVATEUR IRREVERSIBLE : bergamottin

Bergamottin , contenu dans le jus de pamplemousse , est un inhibiteur irréversible à action induite du CYP3A4 intestinal. C’est aussi un inhibiteur du métabolisme de premier passage. Augmentation de la biodisponibilité de certains médicaments.

LA CIGARETTE

  • Induction des CYP1A1 (absent chez les non-fumeurs), CYPA2 et CYP3A4
  • Action médiée par les goudrons du tabac
  • Réduction  des concentrations plasmatiques des substrats des isoenzymes induites
  • Relation possible avec le développement des cancers  du poumon ?
  • Impact sur les concentrations plasmatiques de théophyline (CYP1A2)

LES PLANTES

Millepertuis (herbe de St-jean)

-induction du CYP3A4

-abaissement des concentrations plasmatiques: ciclosporine, indinavir, contraceptifs oraux

– automédication!

DIFFERENCES ETHNIQUES DU POLYMORPHISME DE LA NA T2

 Rapides                Lents 

Esquimaux                                                  95                                 5

Japonais                                                      88                                12

Chinois                                                         78                                22

Latino-Américains                                         70                               30

Noirs Nord -Américains                                 48                               52

Européens et Blancs                                     45                               55

Hindous                                                          40                              60

Egyptiens                                                       17                               83

 

IMPORTANCE CLINIQUE DES INTERACTIONS MEDICAMENTEUSES

  1. Médicaments inactivés par un processus métaboliques :
  • Les inhibiteurs ont tendance à augmenter leurs activité pharmacodynamique
  • Les inducteurs pourront entraîner l’échec thérapeutique

2. Pro-médicaments ou pro-drogues, qui doit être activé par un processus métabolique

  • Les inhibiteurs ont tendance à réduire leurs activités pharmacodynamique
  • Les inducteurs augmentent leurs activités parmacodynamique

3. L’importance clinique des interactions dépend de l’activité et de la toxicité relative du          médicament et de ses métabolites.

4. Les médicaments qui sont substrat de plus d’une enzyme ont en général moins de            risque d’interactions médicamenteuses importantes.

Il existe des voies métaboliques compensatoires

Un équilibre entre  LA PHASE I et LA PHASE II est indispensable pour une détoxication adéquate 

TOXIFICATION PAR LE METABOLISME

Les trois mécanismes principaux de toxification sont:

Formation des radicaux libres

formation d’électrophiles

Activation de l’oxygène moléculaire

Dans une liste de 250 composés chimiques organiques réputés cancérigènes:

Composés à action directe                            10 %

Composés activés par biotransformation       72 %

Cas incertains                                                  18 %

Fréquemment une réaction de toxification est en compétition avec une réaction de détoxification.

Une substance est métabolisée en partie en un métabolite toxique et un métabolite non toxique.

Par exemple :

Le Chloramphénicol (antibiotique ) est métabolisé en 2 parties

Glucuroconjugaison  donne le Glucuronide non toxique 95 %

Déshalogénation réductive en métabolite toxique 5 %

INTOXICATION ou DETOXICATION ?

Le paracétamol :

Détoxication normale par sulphatation et conjugaison avec l’acide glucuronique .

Une overdose diminue les niveaux de sulphate, mais comme les voies de détoxication par le Cytochrome P450 en utilise plus . Il y a production d’un métabolite hépatotoxique.

L’alcool induit les voies du P450 et aggrave donc l’overdose

N-acétyl cystéine antidote

 

INTESTIN ET DETOXICATION

PHASE III : Activité anti-porter ? appelée aussi P-glycoprotéine ou Multi Drug Résistance

L’activité anti-porter est importante pour le métabolisme du premier passage des médicaments et Xénobiotiques

L’anti-porter est une pompe (nécessitant de l’énergie) qui extrait es xénobiotiques à l’extérieure de la cellule et diminue donc leur concentration intracellulaire.

L’activité anti-porter dans les cellules de l’intestin est co-régulée avec le Cyp3A4

SYNDROME DU LEAKY GUT

Un métabolisme de premier passage efficace des xénobiotiques par le tractus intestinal requiert l’intégrité de la barrière intestinale. Si la fonction barrière de la muqueuse est compromise , les xénobiotiques pourront transiter dans la circulation sans avoir eu la possibilité d’être détoxiqués. Un support de la muqueuse intestinale est primordial pour réduire la charge toxique.

Lorsque la fonction barrière intestinale est altérée , le foie subit un surcroît de travail.Le Leaky Gut Syndrome , force le foie à traiter de plus grosses quantité de “toxiques”. Ce stress peut conduire à un état inflammatoire systémique accru.

 

Mécanisme Enzyme impliquée 
Co-facteur 
Lieu 
méthylation méthyltransférase La S-adénosyl-L-méthionine foie, des reins, des poumons, du système nerveux central
sulfatation sulfotransférases 3′-phosphoadénosine-5′-phosphosulfate le foie, le rein, l’intestin
acétylation l’acétyl-coenzyme A le foie, les poumons, la rate, la muqueuse gastrique, les globules rouges , des lymphocytes
glucuronidation UDP-glucuronosyltransférases Acide UDP-glucuronique le foie, les reins, l’intestin, du poumon, de la peau, de la prostate, du cerveau
conjugaison avec le glutathion glutathion-S-transférases glutathion foie, les reins
glycine conjugaison acétyl co-enzyme Comme glycine foie, les reins

 

RÔLE DE LA MICROFLORE INTESTINALE

La microflore intestinale peut produire des composés qui peuvent soit induire soit inhiber les activités de détoxication, les bactéries pathogènes peuvent produire des toxines qui peuvent pénétrer dans la circulation et augmenter la charge toxique.

Le cycle vicieux de la béta-glucuronidase

Dans certains cas de déséquilibre , les bactéries présentes dans le colon produisent l’enzyme Bêta-glucuronidase, qui déconjugue les glucurono-conjugués , avec conséquence un relarguage de molécules toxiques qui auraient dû être éliminées. Surcharge du foie et fatigue , maux de tête , bouche pâteuse , migraine , impression de mal digérer..etc

 

REIN ET DETOXICATION, DETOXICATION ET PH

L’alcalinisation des urines soutient l’élimination urinaire des toxines.

Les phases III utilisent des protéines de transport favorisant l’élimination urinaire des toxines rendues hydrosolubles (phase I et II). Ces protéines sont sensibles au pH

L’apport des citrates en facilitant l’alcalinisation favorise l’élimination des toxines neutralisées dans les urines et dans la bile

Phase 1 study of multiple biomarkers for metabolism and oxidative stress after one-week intake of broccoli sprouts

Phase 1 study of multiple biomarkers for metabolism and oxidative stress after one-week intake of broccoli sprouts

Megumi Murashima1, Shaw Watanabe1, Xing-Gang Zhuo1, Mariko Uehara1, Atsushi Kurashige2

Abstract

 Little is known about the direct effect of broccoli sprouts on human health. So we investigated the effect of broccoli sprouts on the induction of various biochemical oxidative stress markers. Twelve healthy subjects (6 males and 6 females) consumed fresh broccoli sprouts (100 g/day) for 1 week for a phase 1 study. Before and after the treatment, biochemical examination was conducted and natural killer cell activity, plasma amino acids, plasma PCOOH (phosphatidylcholine hydroperoxide), the serum coenzyme Q_{10}, urinary 8-isoprostane, and urinary 8-OHdG (8-hydroxydeoxyguanosine) were measured. With treatment, total cholesterol and LDL cholesterol decreased, and HDL cholesterol increased significantly. Plasma cystine decreased significantly. All subjects showed reduced PCOOH, 8-isoprostane and 8-OHdG, and increased CoQ_{10}H_{2}/CoQ_{10} ratio. Only one week intake of broccoli sprouts improved cholesterol metabolism and decreased oxidative stress markers.

 

 

Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8-hydroxydeoxyguanosine

Phase IIa chemoprevention trial of green tea polyphenols in high-risk individuals of liver cancer: modulation of urinary excretion of green tea polyphenols and 8-hydroxydeoxyguanosine

  1. Jia-Sheng Wang1,*

Abstract

Modulation of urinary excretion of green tea polyphenols (GTPs) and oxidative DNA damage biomarker, 8-hydroxydeoxyguanosine (8-OHdG), were assessed in urine samples collected from a randomized, double-blinded and placebo-controlled phase IIa chemoprevention trial with GTP in 124 individuals. These individuals were sero-positive for both HBsAg and aflatoxin–albumin adducts, and took GTP capsules daily at doses of 500 mg, 1000 mg or a placebo for 3 months. Twenty-four hour urine samples were collected before the intervention and at the first and third month of the study. Urinary excretion of 8-OHdG and GTP components was measured by HPLC-CoulArray electrochemical detection. The baseline levels of 8-OHdG and GTP components among the three groups showed homogeneity (P > 0.70), and a non-significant fluctuation was observed in the placebo group over the 3 months (P > 0.30). In GTP-treated groups, epigallocatechin (EGC) and epicatechin (EC) levels displayed significant and dose-dependent increases in both the 500 mg group and 1000 mg group (P < 0.05). The 8-OHdG levels did not differ between the three groups at the 1 month collection, with medians of 1.83, 2.08 and 1.86 ng/mg-creatinine for placebo, 500 and 1000 mg group, respectively (P = 0.999). At the end of the 3 months’ intervention, 8-OHdG levels decreased significantly in both GTP-treated groups, with medians of 2.02, 1.03 and 1.15 ng/mg-creatinine for placebo, 500 mg and 1000 mg group, respectively (P = 0.007). These results suggest that urinary excretions of EGC and EC can serve as practical biomarkers for green tea consumption in human populations. The results also suggest that chemoprevention with GTP is effective in diminishing oxidative DNA damage.

8-Hydroxy-2'-Deoxyguanosine Is Increased in Epidermal Cells of Hairless Mice after Chronic Ultraviolet B Exposure.

8-Hydroxy-2′-Deoxyguanosine Is Increased in Epidermal Cells of Hairless Mice after Chronic Ultraviolet B Exposure.

Author(s): Hattori, Yukari; Nishigori, Chikako; Tanaka, Tomoyuki; Uchida, Koji; Nikaido, Osamu; Osawa, Toshihiko; Hiai, Hiroshi; Imamura, Sadao; Toyokuni, Shinya

Abstract:8-Hydroxy-2′-deoxyguanosine (8-OhdG) is a mutation-prone (G:C to T:A tranversion) DNA base-modified product generated by reactive oxygen species or photodynamic action. G:C to T:A transversion are observed in the &lt;em&gt;p53&lt;/em&gt; and &lt;em&gt;ras&lt;/em&gt; genes of UVB-induced skin cancers of mice and in squamous and basal cell carcinomas of human skin exposed to sunlight. In the current study, 8-OhdG formation was evaluated in the epidermis of hairless mice after repeated exposure to UVB, and possible mechanisms involved were studied. Exposure of hairless mice to either 3.4 [2 minimal erythema dose (MED)] or 16.8 (10 MED) kJ/m<sup>2</sup> of UVB three times a week for 2 wk induced a 2.5- or 6.1-fold increase, respectively, in the levels of 8-OhdG in DNA, compared to the unexposed controls. An immunohistochemical method using a monoclonal antibody specific for 8-OhdG showed stronger and more extensive staining in the nuclei of UV-irradiated epidermal cells than in those of nonirradiated cells. Western blots probed with antibodies against 4-hydroxy-2-nonenal-modified proteins confirmed the involvement of reactive oxygen species in the epidermal damage induced by chronic UVB exposure. 3-Nitro-L-tyrosine was detected in western blots in a concentration-dependent manner, suggesting that peroxynitrite derived from the reaction of nitric oxide and superoxide, both of which were probably released from inflammatory cells, was involved in modifying the DNA bases. Therefore, the formation of 8-OhdG after UVB exposure appears to be regulated by at least three pathways: photodynamic action, lipid peroxidation, and inflammation and may play a role in sunlight-induced skin carcinogensis.

 

8-hydroxy-2′ -deoxyguanosine (8-OHdG): A Critical Biomarker of Oxidative Stress and Carcinogenesis

8-hydroxy-2′ -deoxyguanosine (8-OHdG): A Critical Biomarker of Oxidative Stress and Carcinogenesis

 Abstract

There is extensive experimental evidence that oxidative damage permanently occurs to lipids of cellular membranes, proteins, and DNA. In nuclear and mitochondrial DNA, 8-hydroxy-2′ -deoxyguanosine (8-OHdG) or 8-oxo-7,8-dihydro-2′ -deoxyguanosine (8-oxodG) is one of the predominant forms of free radical-induced oxidative lesions, and has therefore been widely used as a biomarker for oxidative stress and carcinogenesis. Studies showed that urinary 8-OHdG is a good biomarker for risk assessment of various cancers and degenerative diseases. The most widely used method of quantitative analysis is high-performance liquid chromatography (HPLC) with electrochemical detection (EC), gas chromatography-mass spectrometry (GC-MS), and HPLC tandem mass spectrometry. In order to resolve the methodological problems encountered in measuring quantitatively 8-OHdG, the European Standards Committee for Oxidative DNA Damage was set up in 1997 to resolve the artifactual oxidation problems during the procedures of isolation and purification of oxidative DNA products. The biomarker 8-OHdG or 8-oxodG has been a pivotal marker for measuring the effect of endogenous oxidative damage to DNA and as a factor of initiation and promotion of carcinogenesis. The biomarker has been used to estimate the DNA damage in humans after exposure to cancer-causing agents, such as tobacco smoke, asbestos fibers, heavy metals, and polycyclic aromatic hydrocarbons. In recent years, 8-OHdG has been used widely in many studies not only as a biomarker for the measurement of endogenous oxidative DNA damage but also as a risk factor for many diseases including cancer.