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0|0|le Stablon et l%27Inhibition of mitochondrial beta-oxidation as %E0 mechanism of hepatotoxicity|Paul_L||21:07:49|12/02/2004|[font size="1" color="#5B64B0"]Modifié le 02-12-04 à 21:25  (GMT)[/font][p]%5Bfont size%3D%221%22 color%3D%22%235B64B0%22%5DModifi%E9 le 02-12-04 %E0 21%3A19%A0 %28GMT%29%5B%2Ffont%5D%0D%0A%0D%0ABonjour%2C%0D%0A%0D%0AMoi pr%E9occupent ces %E9tudes sur le Stablon et l%27Inhibition de mitochondrial beta-oxidation comme m%E9canisme de h%E9patotoxicit%E9.%0D%0A%0D%0AS%27il vous pla%EEt quelqu%27un peut expliquer%3F%0D%0A%0D%0AMerci%0D%0A%0D%0A%0D%0A%0D%0A1%3A Pharmacol Ther. 1995%3B67%281%29%3A101-54.%09Related Articles%2C Links %09%0D%0A  %0D%0AInhibition of mitochondrial beta-oxidation as a mechanism of hepatotoxicity.%0D%0A%0D%0AFromenty B%2C Pessayre D.%0D%0A%0D%0AInstitut National de la Sante et de la Recherche Medicale Unite 24%2C Hopital Beaujon%2C Clichy%2C France.%0D%0A%0D%0ASevere and prolonged impairment of mitochondrial beta-oxidation leads to microvesicular steatosis%2C and%2C in severe forms%2C to liver failure%2C coma and death. Impairment of mitochondrial beta-oxidation may be either genetic or acquired%2C 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%2For inhibit mitochondrial beta-oxidation enzymes %28aspirin%2C valproic acid%2C tetracyclines%2C several 2-arylpropionate anti-inflammatory drugs%2C amineptine and tianeptine%29%3B they may inhibit both mitochondrial beta-oxidation and oxidative phosphorylation %28endogenous bile acids%2C amiodarone%2C perhexiline and diethylaminoethoxyhexestrol%29%2C or they may impair mitochondrial DNA transcription %28interferon-alpha%29%2C or decrease mitochondrial DNA replication %28dideoxynucleoside analogues%29%2C while other compounds %28ethanol%2C female sex hormones%29 act through a combination of different mechanisms. Any investigational molecule should be screened for such effects.%0D%0A%0D%0Ahttp%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3DPubMed%26list_uids%3D7494860%26dopt%3DCitation%0D%0A%0D%0A%0D%0A1%3A Biochem Pharmacol. 1989 Nov 1%3B38%2821%29%3A3743-51.%09Related Articles%2C Links %09%0D%0A%0D%0ATianeptine%2C a new tricyclic antidepressant metabolized by beta-oxidation of its heptanoic side chain%2C inhibits the mitochondrial oxidation of medium and short chain fatty acids in mice.%0D%0A%0D%0AFromenty B%2C Freneaux E%2C Labbe G%2C Deschamps D%2C Larrey D%2C Letteron P%2C Pessayre D.%0D%0A%0D%0AUnite de Recherches de Physiopathologie Hepatique %28INSERM U-24%29%2C Hopital Beaujon%2C Clichy%2C France.%0D%0A%0D%0ATianeptine 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%2C tianeptine %280.5 mM%29 inhibited by only 32%25 the formation of beta-oxidation products from %5B1-14C%5Dpalmitic acid by hepatic mitochondria%2C but inhibited by 71%25 that from %5B1-14C%5Doctanoic acid and by 51%25 that from %5B1-14C%5Dbutyric acid. The activity of the tricarboxylic acid cycle%2C assessed as the in vitro formation of %5B14C%5DCO2 from %5B1-14C%5Dacetylcoenzyme A was decreased by 51%25 in the presence of tianeptine %280.5 mM%29. 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%2C administration of tianeptine %280.0625 mmol%2Fkg i.p.%29%2C decreased by 53 and 58%25%2C respectively%2C the formation of %5B14C%5DCO2 from %5B1-14C%5Doctanoic acid and %5B1-14C%5Dbutyric acid%2C but did not significantly decrease that from %5B1-14C%5Dpalmitic acid. After administration of high doses of tianeptine%2C however%2C formation of %5B14C%5DCO2 from %5B1-14C%5Dpalmitic acid became inhibited as well%2C transiently after 0.25 mmol%2Fkg and durably %28greater than 24 hr%29 after 0.75 mmol%2Fkg i.p. Hepatic triglycerides were increased 24 hr after administration of 0.75 mmol%2Fkg i.p. of tianeptine%2C but not after 0.25 mmol%2Fkg i.p. Microvesicular steatosis of the liver was observed in some mice after 0.75 mmol%2Fkg i.p.%2C but not after 0.5 mmol%2Fkg i.p. We conclude that tianeptine inhibits the oxidation of medium- and short-chain fatty acids in mice. Microvesicular steatosis%2C however%2C requires very large doses in mice %280.75 mmol%2Fkg i.p.%2C i.e. 600-times the oral dose in humans%29%2C and is therefore unlikely to occur in humans.%0D%0A%0D%0Ahttp%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3Dpubmed%26list_uids%3D2597170%26dopt%3DCitation %0D%0A%0D%0A
1|1|RE%3A le Stablon et l%27Inhibition of mitochondrial beta-oxidation as %E0 mechanism of hepatotoxicity|Nausica||21:34:21|12/02/2004|[font size="1" color="#5B64B0"]Modifié le 02-12-04 à 21:35  (GMT)[/font][p]Bonsoir%0D%0A%0D%0Aje ne peux rien expliquer%2C %E0 part compl%E9ter votre recherche%3A%0D%0Ac%27est bizarre d%27ailleurs%2C ce monopole de Fran%E7ais sur le coup%21%0D%0A%0D%0Ahttp%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fentrez%2Fquery.fcgi%3Fcmd%3DRetrieve%26db%3Dpubmed%26dopt%3DAbstract%26list_uids%3D7890892%0D%0A%22J Hepatol. 1994 Nov%3B21 %285%29 %3A 771-3. %0D%0A%0D%0A%0D%0ATianeptine--an instance of drug-induced hepatotoxicity predicted by prospective experimental studies.%0D%0A%0D%0ALe Bricquir Y%2C Larrey D%2C Blanc P%2C Pageaux GP%2C Michel H.%0D%0A%0D%0AService d%27Hepato-gastroenterologie Hopital Saint-Eloi%2C Montpellier%2C France.%0D%0A%0D%0AWe report the case of a patient who developed acute hepatitis after taking tianeptine%2C a new tricyclic antidepressant%2C for 8 weeks. Hepatitis exhibited cholangitis-like clinical features and was associated with hypersensitivity manifestations suggestive of an immuno-allergic mechanism. Histological examination showed microvesicular steatosis. The discontinuation of tianeptine administration was followed by complete recovery. Immunoallergic hepatitis and microvesicular steatosis were predicted 2 years ago from prospective experimental studies prompted by the similarity of the chemical structures of tianeptine and amineptine%2C another tricyclic antidepressant%2C well-known for its hepatotoxicity. Experimentally%2C tianeptine has been found to be oxidized into reactive metabolites in several rodents and human liver and to produce microvesicular steatosis probably through inhibition of mitochondrial beta-oxidation of fatty acid in mice. This case illustrates the value of prospectively assessing potential hepatotoxicity mechanisms for new compounds chemically related to drugs already known to be hepatotoxic.%22%0D%0A%0D%0A%0D%0A
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