INFLUENCE OF INDOLE CARBINOLS AND GROWTH-HORMONE ON THE METABOLISM OF4-ANDROSTENEDIONE BY RAT-LIVER MICROSOMES

The effect of indole-3-carbinol (IC), an anticarcinogen present in cru ciferous vegetables, to alter the metabolism of 4-androstenedione (AD) by female rat liver microsomes was investigated and compared to that of its main gastric conversion product, diindolyl-methane (DIM) as wel l as other specific cytochrome P450 inducers. DIM was a more potent in ducer of the hydroxylase which converts androsterone to its 6 beta-hyd roxylated derivative 3 alpha,6 beta-dihydroxy-5 alpha-androstan-17-one (A) than IC after either oral or intraperitoneal administration and w as also a better in vitro inhibitor. Isosafrole (ISF), which like IC a nd DIM, induces CYP1A2 as well as gestodene, were powerful inhibitors of the in vitro reaction. Naringenin produced only a weak inhibitory e ffect while 3-methylcholanthrene was inactive. SKF-525A, a prototypic hydroxylase inhibitor, or 17 beta-N,N-diethylcarbamoyl-4-methyl-4-aza- 5 alpha -androst-1-ene-3-one which inhibits steroid 5 alpha-reductase, also decreased the formation of A from AD by liver microsomes. The in fusion of human growth hormone by osmotic minipump, which feminizes he patic steroid metabolism, increased the ability of male rat liver micr osomes to convert AD to A and to respond to induction by IC. The ident ity of A, the main polar derivative of AD, induced by IC, DIM and ISF, was tentatively assigned by a combination of GC-MS and results from m etabolic studies with intermediates in the pathway leading to its form ation. It is proposed that the protective role of indole carbinols aga inst mammary carcinoma due to decreased formation of 16 alpha-hydroxye strone from estrone may be further enhanced by the diminished availabi lity of AD for aromatization to estrone.