INTERLEUKIN-1-BETA AND INTERLEUKIN-6 REPRESS CLOFIBRIC ACID INDUCTIONOF DIFFERENT P450 ISOFORMS IN CULTURED FETAL-RAT HEPATOCYTES

1. Expression of various P450 subfamilies (1A, 2A, 2B, 2C, 3A) have be en studied in cultured foetal rat hepatocytes after treatment with clo fibric acid, a peroxisome proliferator and prototypic CYP4A inducer in vitro. Ethoxyresorufin O-deethylase activity (EROD, a CYP1A-related a ctivity) as well as 7 alpha-, 16 alpha-, 2 alpha- and 6 beta-testoster one hydroxylase activities (CYP2A, 2B, 2C11 and 3A respectively) were determined during culture. Levels of the corresponding P450 apoprotein s were measured by Western blotting. 2. Clofibric acid was able to ind uce all the P450-dependent activities studied. In most cases this indu ction required the additional presence of dexamethasone, an agent whic h promotes differentiation and favours long-term maintenance of the he patocytes. 3. The major pro-inflammatory cytokines, IL-1 beta and IL-6 , decrease the levels of the clofibric acid-induced P450 isoforms, exc ept CYP1A, which was insensitive to IL-6, previous studies having show n that IL-1 beta represses lauric acid 12-hydroxylase activity after i nduction by clofibric acid. The effects of these cytokines were clearl y dose- and time-dependent, The decrease in enzyme activity correlated with a decrease in apoprotein content. 4. The ability of clofibric ac id to induce P450 isoforms highlights the complexity of P450 regulatio n by peroxisome proliferators. Our results confirm, moreover, that dif ferent P450 subfamilies are differentially affected by IL-1 beta and I L-6.