Effects of hepatotoxic agents on hepatic microsomal metabolism of estrogens in the rat.

Different kinds of experimental liver damage in rats are evaluated as to associated changes in breakdown of natural estrogens. Acute or chronic treatment of rats with ethanol does not influence aromatic hydroxylation of estradiol, as indicated by liver microsomal replacement of tritium from 2,4,6,7-3H-estradiol. More severe liver damage by CCl4 or thioacetamide, which lowers hepatic cytochrome P-450, causes impairment of estrogen degradation: CCl4 dosage leads to a marked decrease in aromatic hydroxylation of estradiol. Whereas thioacetamide in a chronic application schedule has been previously reported to a decrease microsomal aromatic estrogen hydroxylation, a single dose of 300 mg/kg thioacetamide in rats causes increased microsomal formation of estrone from estradiol, which is regarded to be a better (i.e., more lipophilic) substrate for the microsomal estrogen 2-hydroxylase than is estradiol. The data show that hepatotoxic agents may act differentially on hepatic metabolism of endogenous steroids.