The induction of five rat hepatic P450 cytochromes by phenobarbital and similarly acting compounds is regulated by a sexually dimorphic, dietary-dependent endocrine factor that is highly strain specific.
The phenobarbital (PB)-mediated expression of five forms of cytochrome P450 (CYP2A1, CYP2B1, CYP2B2, CYP2C6, and CYP3A1) and epoxide hydrolase has been examined in male and female rats from three inbred strains [Fischer (F344), Wistar Furth (WF), and Wistar Kyoto (WK)]. Evidence is presented that the regulation of induction of each protein involves a very similar endocrine control process. Each induction shows the same marked strain differences that are observable to a much greater extent in females than in males. The differences are largely removed by hypophysectomy and are each greatly enhanced by a shift in diet (standard [Teklad (W) 8604] to defined [Teklad AIN-76A]). The induction of each gene in female rats, as measured by specific immunoblots, follows the same strain selectivity (F344 >> WK > WF). These differences were similarly demonstrated in isoform-specific metabolism and comparable variations in the levels of the specific P450 mRNA suggest that these differences reflect alterations in gene transcription. For CYP3A1, CYP2B1, and CYP2B2, the differences between the F344 and WF strains approach 10-fold when using the defined diet, while the differences decreased approximately 3-fold with the standard chow, in parallel with much more effective induction of total P450. The same trend was also observed for the induction of CYP2A1, CYP2C6, and epoxide hydrolase, but the differences were less because of higher constitutive levels which were insensitive to these effects and smaller induction factors. These strain differences were not observed for CYP1A2, which is unresponsive to PB. Similar sex- and strain-selectivity for each P450 gene occurs for D-limonene, a structurally and chemically dissimilar PB-type inducer. Each of these measurements indicates a suppression of expression in female WF rats relative to a set of similar levels in male WF rats and F344 rats of both sexes. Hypophysectomy relieves the suppression through selective stimulation of induced levels in female WF rats. Many of the same differences between the F344 and WF strains can be observed in the very low basal expression of these PB-inducible genes. Thus, we have identified a gender-selective, pituitary-mediated polymorphism that probably affects basal regulatory factors.
Environmental Toxicology Center, University of Wisconsin, Madison 53706.
M C
MC
Larsen
P B
PB
Brake
D
D
Parmar
C R
CR
Jefcoate
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D001483:Base Sequence; D053138:Cyclohexenes; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis*; D005260:Female; D007016:Hypophysectomy; D000077222:Limonene; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D008969:Molecular Sequence Data; D009752:Nutritional Status; D010634:Phenobarbital / Q000494:pharmacology*; D010902:Pituitary Gland / Q000502:physiology; D011110:Polymorphism, Genetic; D051381:Rats; D011919:Rats, Inbred Strains / Q000502:physiology*; D017208:Rats, Wistar; D012727:Sex Characteristics; D013045:Species Specificity; D013729:Terpenes / Q000494:pharmacology; D015262:Xenobiotics / Q000494:pharmacology
D053138:Cyclohexenes; D013729:Terpenes; D015262:Xenobiotics; D003577:Cytochrome P-450 Enzyme System; D000077222:Limonene; D001189:Aryl Hydrocarbon Hydroxylases; C465138:Cyp3a23-3a1 protein, rat; D051544:Cytochrome P-450 CYP3A; D004851:Epoxide Hydrolases; D010634:Phenobarbital