THE INDUCTION OF 5 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 hydrola se 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 sa me marked strain differences that are observable to a much greater ext ent in females than in males. The differences are largely removed by h ypophysectomy and are each greatly enhanced by a shift in diet (standa rd [Teklad (W)8604] to defined [Teklad AIN-76A]). The induction of eac h gene in female rats, as measured by specific immunoblots, follows th e same strain selectivity (F344 much greater than WK > WF). These diff erences 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 P344 and WF s trains approach 10-fold when using the defined diet, while the differe nces decreased approximately 3-fold with the standard chow, in paralle l with much more effective induction of total P450. The same trend was also observed for the induction of CYP2A1, CYP2C6, and epoxide hydrol ase, but the differences were less because of higher constitutive leve ls which were insensitive to these effects and smaller induction facto rs. These strain differences were not observed for CYP1A2, which is un responsive to PB. Similar sex- and strain-selectivity for each P450 ge ne occurs for D-limonene, a structurally and chemically dissimilar PB- type inducer. Each of these measurements indicates a suppression of ex pression in female WF rats relative to a set of similar levels in male WF rats and F344 rats of both sexes. Hypophysectomy relieves the supp ression through selective stimulation of induced levels in female WF r ats. Many of the same differences between the F344 and WF strains can be observed in the very low basal expression of these PB-inducible gen es. Thus, we have identified a gender-selective, pituitary-mediated po lymorphism that probably affects basal regulatory factors. (C) 1994 Ac ademic Press, Inc.