Jellinck P H, Makin H L, Sepkovic D W, Bradlow H L
Department of Biochemistry, Queen's University, Kingston, Ontario, Canada.
J Steroid Biochem Mol Biol. 1993 Dec;46(6):791-8. doi: 10.1016/0960-0760(93)90320-v.
The effect of indole-3-carbinol (IC), an anticarcinogen present in cruciferous 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, diindolylmethane (DIM) as well as other specific cytochrome P450 inducers. DIM was a more potent inducer of the hydroxylase which converts androsterone to its 6 beta-hydroxylated derivative 3 alpha, 6 beta-dihydroxy-5 alpha-androstan-17-one (A) than IC after either oral or intraperitoneal administration and was also a better in vitro inhibitor. Isosafrole (ISF), which like IC and DIM, induces CYP1A2 as well as gestodene, were powerful inhibitors of the in vitro reaction. Naringenin produced only a weak inhibitory effect 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 infusion of human growth hormone by osmotic minipump, which feminizes hepatic steroid metabolism, increased the ability of male rat liver microsomes to convert AD to A and to respond to induction by IC. The identity 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 metabolic studies with intermediates in the pathway leading to its formation. It is proposed that the protective role of indole carbinols against mammary carcinoma due to decreased formation of 16 alpha-hydroxyestrone from estrone may be further enhanced by the diminished availability of AD for aromatization to estrone.
研究了十字花科蔬菜中存在的抗癌物质吲哚 - 3 - 甲醇（IC）对雌性大鼠肝微粒体改变4 - 雄烯二酮（AD）代谢的影响，并将其与主要胃转化产物二吲哚甲烷（DIM）以及其他特定细胞色素P450诱导剂的影响进行了比较。口服或腹腔注射后，DIM比IC更有效地诱导将雄甾酮转化为其6β - 羟基化衍生物3α，6β - 二羟基 - 5α - 雄甾烷 - 17 - 酮（A）的羟化酶，并且也是更好的体外抑制剂。异黄樟素（ISF）与IC和DIM一样，可诱导CYP1A2以及孕二烯酮，是体外反应的强力抑制剂。柚皮素仅产生微弱的抑制作用，而3 - 甲基胆蒽无活性。原型羟化酶抑制剂SKF - 525A或抑制类固醇5α - 还原酶的17β - N，N - 二乙基氨基甲酰基 - 4 - 甲基 - 4 - 氮杂 - 5α - 雄甾 - 1 - 烯 - 3 - 酮也降低了肝微粒体由AD形成A的能力。通过渗透微型泵输注人生长激素可使肝脏类固醇代谢女性化，增加了雄性大鼠肝微粒体将AD转化为A以及对IC诱导作出反应的能力。通过气相色谱 - 质谱联用以及对导致其形成途径中中间体的代谢研究结果，初步确定了由IC、DIM和ISF诱导产生的AD主要极性衍生物A的身份。有人提出，由于从雌酮形成16α - 羟基雌酮的减少，吲哚甲醇对乳腺癌的保护作用可能会因用于芳香化生成雌酮的AD可用性降低而进一步增强。
