Restoration of cytochrome P450 2C11 in vitamin A-deficient rat liver by exogenous androgen.
Down-regulation of microsomal androgen-dependent CYP2C11 is produced in male rat liver by dietary vitamin A deficiency. Decreased circulating androgen concentrations also occur in vitamin A-deficient male rats. Both effects are prevented by addition of all-trans-retinoic acid to the diet. The present study evaluated directly whether androgen deficiency may be responsible for the down-regulation of 2C11 in vitamin A-deficient male rats. The major finding was that subcutaneous administration of the androgen methyltrienolone (MT) during the final week of the study restored CYP2C11 protein and its associated steroid 16alpha-hydroxylation activities to control levels; CYP2C11 mRNA was also restored. Despite the efficient restoration of CYP2C11 at a pretranslational level, no alteration in vitamin A status was apparent and animals remained vitamin A deficient after MT treatment. The possibility was assessed that vitamin A can maintain the microsomal content of CYP2C11 in normal liver. However, in contrast to MT, administration of ATRA to gonadectomized male rats did not restore 2C11 in liver. These findings establish that the major effect of vitamin A deficiency on CYP2C11 in male rat liver is mediated indirectly by androgen deficiency.
Murray
M
M
Storr Liver Unit, Department of Medicine, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
Butler
A M
AM
Agus
C
C
D000735:Androstenedione / Q000378:metabolism; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D004032:Diet; D015536:Down-Regulation; D006900:Hydroxylation; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D015741:Metribolone / Q000494:pharmacology*; D008862:Microsomes, Liver / Q000201:enzymology; D009752:Nutritional Status; D009919:Orchiectomy; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D039181:Steroid 16-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D045165:Testosterone Congeners / Q000494:pharmacology*; D014212:Tretinoin / Q000494:pharmacology; D014802:Vitamin A Deficiency / Q000201:enzymology*
D012333:RNA, Messenger; D045165:Testosterone Congeners; D015741:Metribolone; D000735:Androstenedione; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C450279:CYP2C11 protein, rat; D000072467:Cytochrome P450 Family 2; D039181:Steroid 16-alpha-Hydroxylase