Murray M, Cantrill E, Farrell G C
Department of Medicine, University of Sydney, Westmead Hospital, NSW, Australia.
J Steroid Biochem. 1988 Feb;29(2):233-7. doi: 10.1016/0022-4731(88)90271-3.
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.
这些研究的目的是确定雌激素生成是否是雄甾-4-烯-3,17-二酮肝微粒体代谢中一条具有重要定量意义的途径。在体外对大鼠研究了酶诱导剂苯巴比妥和β-萘黄酮对微粒体细胞色素P-450介导的雄甾-4-烯-3,17-二酮羟基化和芳香化的影响。在未处理大鼠的微粒体组分中，羟基化产物与芳香化（雌激素）代谢物的比例为33:1。对大鼠进行苯巴比妥预处理可使总羟基化增加约20%，但未改变羟基化产物与芳香化产物的比例（27:1）。相比之下，β-萘黄酮诱导使总羟基化降至对照的约35%，但不影响总芳香化。因此，羟基化与芳香化的比例显著低于对照微粒体（17:1）。主要的芳香化产物是雌三醇和2-羟基雌二醇-17β，雌二醇-17β及其4-羟基代谢物为次要产物；未观察到雌酮。在对雌酮微粒体代谢的进一步研究中，主要产物是雌二醇-17β，而羟基化代谢物只是次要产物。相比之下，雌二醇-17β有相当程度的羟基化。这些发现表明，雌酮作为微粒体17β-氧化还原酶的底物比作为细胞色素P-450的底物更好。因此，由雄甾-4-烯-3,17-二酮芳香化形成的任何雌酮似乎都很容易转化为雌二醇-17β，而雌二醇-17β又会受到细胞色素P-450介导的羟基化作用。虽然肝脏是C19-类固醇芳香化的场所，但由于微粒体羟化酶能够轻易地将芳香化产物转化为无生物活性的代谢物，该器官似乎不太可能对血清雌激素水平有显著贡献。
