Hepatic microsomal metabolism of androst-4-ene-3,17-dione: relative importance of ring hydroxylation and aromatization in control and induced rat liver.
The purpose of these studies was to determine whether oestrogen production is a quantitatively important pathway in the hepatic microsomal metabolism of androst-4-ene-3,17-dione. The effects of the enzyme inducing agents phenobarbitone and beta-naphthoflavone on microsomal cytochrome P-450-mediated androst-4-ene-3,17-dione hydroxylation and aromatization was investigated in the rat in vitro. In microsomal fractions from untreated rats the ratio of hydroxylated products to aromatized (oestrogenic) metabolites was 33:1. Phenobarbitone pretreatment of rats increased total hydroxylation by about 20% but did not change the ratio of hydroxylated to aromatized products (27:1). In contrast, beta-naphthoflavone induction decreased total hydroxylation to about 35% of control but did not affect total aromatization. Thus the ratio of hydroxylation to aromatization was significantly lower than in control microsomes (17:1). The principal aromatized products were oestriol and 2-hydroxyoestradiol-17 beta, with oestradiol-17 beta and its 4-hydroxy metabolite as minor products; no oestrone was observed. In further studies of the microsomal metabolism of oestrone, the major product was oestradiol-17 beta whereas hydroxylated metabolites were only minor products. Oestradiol-17 beta, in contrast, was hydroxylated to a considerable extent. These findings suggest that oestrone is a better substrate for the microsomal 17 beta-oxidoreductase than it is for cytochrome P-450. It therefore appears likely that any oestrone formed from the aromatization of androst-4-ene-3,17-dione would be readily converted to oestradiol-17 beta which, in turn, is subject to cytochrome P-450-mediated hydroxylation. Although the liver is a site of C19-steroid aromatization, it appears unlikely that this organ could contribute significantly to serum oestrogen levels since microsomal hydroxylases are readily able to convert aromatized products to biologically inactive metabolites.
Murray
M
M
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
Cantrill
E
E
Farrell
G C
GC
D000735:Androstenedione / Q000378:metabolism*; D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004958:Estradiol / Q000378:metabolism; D004970:Estrone / Q000378:metabolism; D006900:Hydroxylation; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D004970:Estrone; D000735:Androstenedione; D004958:Estradiol; D019324:beta-Naphthoflavone; D003577:Cytochrome P-450 Enzyme System; D010634:Phenobarbital