title: Pretranslational down-regulation of male specific hepatic P450s after portal bypass.
abstract: 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.
authors.affiliation: Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
authors.forename: X M
authors.initials: XM
authors.lastname: Jiang
authors.forename: E
authors.initials: E
authors.lastname: Cantrill
authors.forename: G C
authors.initials: GC
authors.lastname: Farrell
authors.forename: M
authors.initials: M
authors.lastname: Murray
mesh_terms: D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D007527:Isoenzymes / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D008969:Molecular Sequence Data; D011169:Portal Vein / Q000601:surgery; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012737:Sex Factors; D013737:Testis / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism
chemical_list: D004967:Estrogens; D007527:Isoenzymes; D012333:RNA, Messenger; D013739:Testosterone; D000735:Androstenedione; D003577:Cytochrome P-450 Enzyme System