Diversion of portal blood away from the liver in the portal vein ligated (PVL) male rat results in dysfunction of the hypothalamo-pituitary-gonadal axis, as reflected by an increase in circulating oestradiol, a decrease in serum testosterone and decreased expression of the male-specific cytochrome P450 2C11 in hepatic microsomes. The present study assessed whether there was a decline in the hepatic concentrations of mRNA species corresponding to male-specific P450s and whether female-specific hepatic enzymes may be upregulated after PVL. In microsomes from PVL male rat liver the activities of P450s 2C11 and 3A2 (androstenedione 16 alpha- and 6 beta-hydroxylation, respectively) were decreased to 45% (P < 0.001) and 43% (P < 0.002) of control. Slot blotting revealed a decline in the mRNAs for P450 2C11 and 3A2 to 46 +/- 7 and 27 +/- 4% of respective control (relative to beta-actin mRNA). In contrast, mRNAs for the female specific P450 2C12 and delta 4-ketosteroid-5 alpha-oxidoreductase were unchanged from control (100 +/- 13% and 122 +/- 28%, respectively). P450 2C12 protein was not detected in either control or PVL male rat liver but a slight increase in the rate of 5 alpha-dihydrotestosterone formation was noted after PVL (2.95 +/- 0.40 vs 1.00 +/- 0.22 nmol/min/mg protein, P < 0.05; corresponding, respectively, to 30 and 10% of the activity in female liver microsomes). These studies indicate that the male-specific P450 2C11 and 3A2 are down-regulated at a pretranslational level whereas upregulation of the female-specific enzymes P450 2C12 and delta 4-ketosteroid-5 alpha-oxidoreductase does not occur after PVL. Thus, the endocrine effects of portal bypass result in biochemical demasculinization, but not feminization, of hepatic enzymes involved in steroid biotransformation. Because male-specific P450s are effective steroid hydroxylating enzymes, their down regulation after PVL would significantly decrease hepatic androgen extraction.