Regulation of phase I and phase II steroid metabolism enzymes by PPAR alpha activators.

Peroxisome proliferators (PP) are a large class of structurally diverse chemicals that mediate their effects in the liver mainly through the peroxisome proliferator-activated receptor alpha (PPARalpha). Exposure to some PP results in alterations of steroid levels that may be mechanistically linked to adverse effects in reproductive organs. We hypothesized that changes in steroid levels after PP exposure are due to alterations in the levels of P450 enzymes that hydroxylate testosterone and estrogen. In testosterone hydroxylase assays, exposure to the PP, WY-14,643 (WY), gemfibrozil or di-n-butyl phthalate (DBP) led to compound-specific increases in 6beta and 16beta-testosterone and androstenedione hydroxylase activities and decreases in 16alpha, 2alpha-hydroxylase activities by all three PP. The decreases in 16alpha and 2alpha-testosterone hydroxylase activity can be attributed to a 2alpha and 16alpha- testosterone hydroxylase, CYP2C11, which we previously showed was dramatically down-regulated in these same tissues (Corton et al., 1998; Mol. Pharmacol. 54, 463-473). To explain the increases in 6beta- and 16beta-testosterone hydroxylase activities, we examined the expression of P450 family members known to carry out these functions. Alterations in the 6beta-testosterone hydroxylases CYP3A1, CYP3A2 and the 16beta-testosterone hydroxylase, CYP2B1 were observed after exposure to some PP. The male-specific estrogen sulfotransferase was down-regulated in rat liver after exposure to all PP. The mouse 6beta-testosterone hydroxylase, Cyp3a11 was down-regulated by WY in wild-type but not PPARalpha-null mice. In contrast, DEHP increased Cyp3a11 in both wild-type and PPARalpha-null mice. These studies demonstrate that PP alter the expression and activity of a number of enzymes which regulate levels of sex steroids. The changes in these enzymes may help explain why exposure to some PP leads to adverse effects in endocrine tissues that produce or are the targets of sex hormones.