Opposing mechanisms of NADPH-cytochrome P450 oxidoreductase regulation by peroxisome proliferators

Peroxisome proliferators (PPs) regulate a battery of rodent P450 genes, including CYP2B, CYP2C, and CYNA family members. We hypothesized that other components of the P450-metabolizing system are altered by exposure to PP's, including NADPH-cytochrome P450 oxidoreductase (P450R), an often rate-limiting component in P450-dependent reactions. In this study, we determined whether exposure to structurally diverse PPs alters the expression of P450R mRNA and protein. Increases in P450R mRNA levels were observed in male and female F-344 rat livers and in male rat kidneys after chronic exposure of the animals to PPs. Paradoxically, under the same treatment conditions in male rats, liver P450R protein levels decreased after exposure to the PPs Wy-14,643 ([4-chloro-6-(2,3-xylidino)pyrimidynylthiol acetic acid) (WY) or gemfibrozil (GEM). The down-regulation of the P450R protein was sex- and tissue-specific in that exposure to PPs led to increases in P450R protein in female rat livers [di-n-butyl phthalate (DBP) only] and male rat kidneys (WY, GEM, DBP). In male wild-type SV129 mice, P450R mRNA levels increased in livers after exposure to WY and diethylhexyl phthalate (DEHP) and in male kidneys after exposure to DEHR Induction of mRNA by PPs was not observed in the liver or kidneys of mice, which lack a functional peroxisome proliferator-activated receptor alpha(PPARalpha), the central mediator of the effects of PPs in the rodent liver. In wild-type male mice, P450R protein was decreased in liver after WY and DEHP treatment and in kidneys after WY treatment. The down-regulation of the P450R protein was not observed in PPARalpha-null mice. These studies demonstrate the complex regulation of P450R expression by PPs at two different levels, both of which are dependent upon PPARalpha: up-regulation of transcript levels in liver and kidneys and down-regulation of protein levels in male rat and mouse liver by a novel posttranscriptional mechanism. (C) 2003 Elsevier Science Inc. All rights reserved.