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Effect of irradiation on the activity of the major P450 cytochromes implicated in the biosynthesis of bile acids


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Maâmar Souidi, Pascale Scanff, Stéphane Grison, Nina M Griffiths, Michel Parquet, Michel Riottot, Jocelyne Aigueperse 12th internat.conf. on cytochrome P450, La Grande Motte (France), 11-15/09/2001

Résumé

Exposure to ionising radiation results in severe alterations of biliary physiology which are manifested in particular by changes in the profiles of bile acids that are released into the gut via the bile. These changes may contribute to radio-induced gastrointestinal damage and subsequent diarrhoea. Among mechanisms that may be implicated in the change of the profiles, alteration of intestinal bile acid reabsorption and modification of hepatic bile acid biosynthesis are probably the major ones. Hepatic biosynthesis of bile acids from cholesterol is dependent on enzymes of the P450 cytochrome family according to two major pathways. In the neutral (classic) pathway biosynthesis is initiated by the microsomal cholesterol 7alpha-hydroxylase (CYP7A1) and in the acidic (alternative) pathway by the mitochondrial cholesterol 27-hydroxylase (CYP27A1) and the microsomal oxysterol 7alpha-hydroxylase (CYP7B1).In man and in some experimental animals these two synthetic pathways result in the production of chenodeoxycholic acid (CDCA) or to cholic acid (CA) after hydroxylation by the microsomal sterol 12alpha-hydroxylase (CYP8B1). Thus, the aim of this work was to determine the activities of these four major enzymes implicated in bile acid biosynthesis (CYP7A1, CYP27A1, CYP7B1 and CYP8B1) after exposure to ionising radiation. This study was carried out in the rat 4 days after a whole body 8 Gy gamma 60Co irradiation. In the liver, irradiation leads to a decreased activity of CYP7A1 (-51%) and CYP7B1 (-90%). On the other hand, activity of both CYP27A1 and CYP8B1 was not modified by irradiation. Concomitantly, in the bile, changed proportions of individual bile acids in the pool of total bile salts were observed: ratio CA/CDCA was increased (x2.7). These results show, for the first time, that exposure to ionising radiation leads to an inhibition of the two "7alpha-hydroxylase" CYP7A1 and CYP7B1 microsomal P450 cytochrome activities. This change participates probably in the changed profile observed in the bile of irradiated rats. Moreover, it suggests that irradiation which modifies enterohepatic recirculation of bile salts by decreasing intestinal bile salt reabsorption also alters metabolism of bile acids by affecting some of the major enzymatic activities implicated in their biosynthesis. This work was done in collaboration with "Université d'Orsay".