DOWN-REGULATION OF CYTOCHROME-P450 2C FAMILY MEMBERS AND POSITIVE ACUTE-PHASE RESPONSE GENE-EXPRESSION BY PEROXISOME PROLIFERATOR CHEMICALS

In this study, we show that peroxisome proliferator chemical (PPC) exp osure leads to alterations in the expression of genes in rat liver reg ulated by the sex-specific growth hormone secretory pattern and induce d during inflammation. Expression of the male-specific cytochrome P450 (P450) 2C11 and alpha 2 urinary globulin (alpha 2u) genes and the fem ale-specific P450 2C12 gene was down-regulated by some PPC. Expression of P450 2C13, also under control by the sex-specific growth hormone s ecretory pattern, was not altered by PPC treatment, indicating that re gulation of CYP2C family members does not involve perturbation of the growth hormone secretory pattern. In contrast to the increases in expr ession observed when inflammation was induced in male rats, two positi ve acute-phase response genes, alpha(1)-acid glycoprotein and beta-fib rinogen, were decreased by PPC exposure. The down-regulation of the P4 50 2C11 by WY-14,643 could be reproduced in cultured rat hepatocytes, indicating the down-regulation is a direct effect. Experiments in wild -type mice and mice that lacked a functional peroxisome proliferator-a ctivated receptor-alpha gene showed that down-regulation by WY of alph a(1)-acid glycoprotein, beta-fibrinogen, and a mouse homologue of alph a 2u was dependent on peroxisome proliferator-activated receptor-alpha expression. Our results demonstrate that PPC exposure leads to down-r egulation of diverse liver-specific genes, including CYP2C family memb ers important in hormonal homeostasis and acute-phase response genes i mportant in inflammatory responses.