Effect of tumor promoting contraceptive steroids on growth and drug metabolizing enzymes in rat liver.

Liver tumor formation in rats treated with oral contraceptive steroids for long periods has been associated with the tumor promoting potential of these agents. As other known liver tumor promoters, e.g., phenobarbital and hexachlorocyclohexane, induce liver growth and hepatic monooxygenases, we investigated whether or not estrogens have similar effects. Female rats were treated with a wide range of doses of ethinylestradiol, including human contraceptive doses, which are approximately 1 microgram/kg. The physiological estrogen estradiol was studied for comparison. Also included were norethynodrel and norethisteron and its acetate and enanthate because these human progestins act predominantly estrogenic in rats. Daily s.c. doses of ethinylestradiol (0.5 mg/kg) produced a rapid increase of liver mass, DNA, RNA, and protein which was almost maximal after 7 days. The percentages of parenchymal cells involved in DNA synthesis and mitosis were enhanced up to 20-fold, suggesting parenchymal hyperplasia as the main cause of liver growth. Sinus wall cells showed a proportionate increase of number and DNA synthesis. Likewise, all other steroids tested produced significant increases of liver mass and DNA. For ethinylestradiol and estradiol extrapolated threshold doses were in the range of 1 microgram/kg. These doses are below those used in previous tumor promotion studies in rats. Using 5 different substrates to check monooxygenase activities of isolated liver microsomes, no induction or only very weak induction by estrogens was found. These studies suggest that induction of liver growth may be a property relevant for the tumor promoting activity of estrogens; in contrast, induction of hepatic monooxygenases does not appear to be necessary for liver tumor promotion in the rat.