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Quantitative Structure-Activity Studies on Effects of Sixteen Different Steroids on Growth and Monooxygenases of Rat Liver

Institut für Toxikologie und Pharmakologie der Philipps-Universität, Pilgrimstein 2, D-3550 Marburg Federal Republic of Germanyand Institut für Tumorbiologie-Krebsforschung der Universität Wien, Borschkegasse 8a, A-1090 Wien, Austria

Sixteen steroids with different endocrine activities were administered to female rats for 6 or 7 days, in a broad range of doses. Liver growth was recorded by measuring weight and DNA contents and monooxygenase activity by assaying the turnover of five different substrates. According to their effects on these parameters steroids were assigned into one of the following three groups: (a) Estrogens estradiol and ethinylestradiol, as well as the progestins norethynodrel and norethisterone (norethindrone) which have estrogenic activity in rats. These agents induced pronounced liver growth and excessive DNA increase which was not associated with major monooxygenase induction. (b) A different type of response consisted of liver growth and DNA increase associated with a pronounced induction of monooxygenase(s) in a characteristic pattern. This response was elicited by pregnenolone-16 -carbonitril, by progestins progesterone, cyproterone acetate, and medroxyprogesterone (but not gestoden and levo-norgestrel), by the antimineralocorticoid spironolactone and by the glucocorticoids cortisol and dexamethasone. Apparently, this response pattern was not related to any specific endocrine action but to certain structural features, in particular to the presence of a saturated, at least two-membered alkyl substituent at C17 of the steroid ring system. (c) No or small effects were observed after gestoden, levonorgestrel and the androgens testosterone and methyltestosterone.

Dose-response studies revealed that estrogens estradiol and EE₂ induced hepatic effects more potently by four orders of magnitude than progestins. The response patterns observed may be relevant to the tumorpromoting activity of some of the steroids tested.

¹ To whom requests for reprints should be addressed, at Institut für Tumorbilogie-Krebsforschung der Universität Wien, Borschkegasse 8a, A-1090 Wien, Austria

² Present address: Universitäts-Frauenklinik, Albert-Schweitzer Straffie 33, D-44 Münster, Federal Republic of Germany.

Received 7/20/87. Revised 12/23/87. Accepted 1/28/88.

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