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Mécanisme des hépatites immunoallergiques induites par l'acied tiénilique : Activation métabolique de ce médicament et fixation covalente sur les cytochromes P4502C chez l'homme et le rat

Eric Bonierbale 1
1 CBPT
LCBPT - UMR 8601 - Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques
Abstract : The increasing number of hospitalizations due to drug induced toxic effects secondary to a drug treatment is a major problem of public health. Drug induced hepatitis, the most frequent iatrogenic problem is also an economic problem. Drug induced hepatotoxicity is the first cause of market withdrawal. Non detection of the hepatotoxic potential before lauch of a drug is mostly due to the idiosyncratic toxicity . Drug induced hepatitis can be divided in two groups. Direct hepatitis and immunoallergic hepatitis. The mechanism of idiosyncratic reactions is not well known, and progress in its comprehension is needed for reasons of economics and public health. My work has consisted into understanding the first steps of the appearance of idiosyncratic hepatitis, and in particular of that due to tienilic acid (TA). This uricosuric diuretic was withdrawn in 1992 and was responsible of a number of immunoallergic cytolytic hepatitis. Patient sera contained anti-tissue antibodies called Anti-LKM2 (anti-LiverKidneyMicrosome2). These antibodies specifically recognize CYP2C9 a human cytochrome P450 responsible for TA metabolisation. The major results of my study are : Tienilic acid activation by human liver microsomes leads to a reactive metabolite which binds covalently to hepatic proteins. The isomer of tienilic acid TAI is activated to a thiophen sulfoxide which react with protein nucleophiles to covalent adducts. Both adductThe formation of reactive metabolite, possibly a thiophen S-oxide of TA may constitute the first step of TA drug induced hepatitis. Wehave shown that TA activation into covalent adducts by human liver microsomes is very specific: CYP2C9 is the major target. Thus CYP2C9 alkylation could be the second step of its drug induced hepatitis. We have also shown that CYP2C11 the homologous P450 in rat is the target of TA covalent binding both in vitro and in vivo. In rat liver the TA adducts are localized on the centrolobular area. This major alkylation of centrolobular hepatocytes could favorize the presentation of adducted proteins to blood immunocompetent cells, and thus constitute the third step in drug induced hepatitis. Finally we show that all patients treated with TA have circulating antibodies directed against TA bound to proteins.
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Submitted on : Wednesday, December 21, 2011 - 5:28:58 PM
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  • HAL Id : tel-00654392, version 1

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Eric Bonierbale. Mécanisme des hépatites immunoallergiques induites par l'acied tiénilique : Activation métabolique de ce médicament et fixation covalente sur les cytochromes P4502C chez l'homme et le rat. Toxicologie. Université René Descartes - Paris V, 1996. Français. ⟨tel-00654392⟩

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