Modifié le 02-12-04 à 21:25 (GMT)Modifié le 02-12-04 à 21:19 (GMT)
Bonjour,
Moi préoccupent ces études sur le Stablon et l'Inhibition de mitochondrial beta-oxidation comme mécanisme de hépatotoxicité.
S'il vous plaît quelqu'un peut expliquer?
Merci
1: Pharmacol Ther. 1995;67(1):101-54. Related Articles, Links
Inhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity.
Fromenty B, Pessayre D.
Institut National de la Sante et de la Recherche Medicale Unite 24, Hopital Beaujon, Clichy, France.
Severe and prolonged impairment of mitochondrial beta-oxidation leads to microvesicular steatosis, and, in severe forms, to liver failure, coma and death. Impairment of mitochondrial beta-oxidation may be either genetic or acquired, and different causes may add their effects to inhibit beta-oxidation severely and trigger the syndrome. Drugs and some endogenous compounds can sequester coenzyme A and/or inhibit mitochondrial beta-oxidation enzymes (aspirin, valproic acid, tetracyclines, several 2-arylpropionate anti-inflammatory drugs, amineptine and tianeptine); they may inhibit both mitochondrial beta-oxidation and oxidative phosphorylation (endogenous bile acids, amiodarone, perhexiline and diethylaminoethoxyhexestrol), or they may impair mitochondrial DNA transcription (interferon-alpha), or decrease mitochondrial DNA replication (dideoxynucleoside analogues), while other compounds (ethanol, female sex hormones) act through a combination of different mechanisms. Any investigational molecule should be screened for such effects.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=7494860&dopt=Citation
1: Biochem Pharmacol. 1989 Nov 1;38(21):3743-51. Related Articles, Links
Tianeptine, a new tricyclic antidepressant metabolized by beta-oxidation of its heptanoic side chain, inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice.
Fromenty B, Freneaux E, Labbe G, Deschamps D, Larrey D, Letteron P, Pessayre D.
Unite de Recherches de Physiopathologie Hepatique (INSERM U-24), Hopital Beaujon, Clichy, France.
Tianeptine is a new tricyclic antidepressant which is metabolized mainly by beta-oxidation of its heptanoic side chain. We determined the effects of tianeptine on the mitochondrial oxidation of natural fatty acids in mice. In vitro, tianeptine (0.5 mM) inhibited by only 32% the formation of beta-oxidation products from <1-14C>palmitic acid by hepatic mitochondria, but inhibited by 71% that from <1-14C>octanoic acid and by 51% that from <1-14C>butyric acid. The activity of the tricarboxylic acid cycle, assessed as the in vitro formation of <14C>CO2 from <1-14C>acetylcoenzyme A was decreased by 51% in the presence of tianeptine (0.5 mM). The inhibition of both beta-oxidation and the tricarboxylic acid cycle appeared reversible in mitochondria from mice exposed to tianeptine in vivo but incubated in vitro without tianeptine. In vivo, administration of tianeptine (0.0625 mmol/kg i.p.), decreased by 53 and 58%, respectively, the formation of <14C>CO2 from <1-14C>octanoic acid and <1-14C>butyric acid, but did not significantly decrease that from <1-14C>palmitic acid. After administration of high doses of tianeptine, however, formation of <14C>CO2 from <1-14C>palmitic acid became inhibited as well, transiently after 0.25 mmol/kg and durably (greater than 24 hr) after 0.75 mmol/kg i.p. Hepatic triglycerides were increased 24 hr after administration of 0.75 mmol/kg i.p. of tianeptine, but not after 0.25 mmol/kg i.p. Microvesicular steatosis of the liver was observed in some mice after 0.75 mmol/kg i.p., but not after 0.5 mmol/kg i.p. We conclude that tianeptine inhibits the oxidation of medium- and short-chain fatty acids in mice. Microvesicular steatosis, however, requires very large doses in mice (0.75 mmol/kg i.p., i.e. 600-times the oral dose in humans), and is therefore unlikely to occur in humans.
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&list_uids=2597170&dopt=Citation
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