Ethynylestradiol-induced Impairment of Bile Secretion in the Rat: Protective Effects of S-adenosyl-L-methionine and Its Implication in Estrogen Metabolism

Previous investigations demonstrated that S-adenosyl-L-methionine suppresses the cholestatic effect of ethynylestradiol and reduces the irreversible binding of the estrogen to rat liver microsomes, probably favoring ethynylestradiol transformation into its methyl-derivatives. Since it is not known whether SAMe also prevents the changes of bile lipid composition induced by EE and how methylation interferes with estrogen metabolism and biliary excretion, female rats have been treated with ethynylestradiol (5 mg/kg body wt, orally for 3 days) or with ethynylestradiol plus S-adenosyl-L-methionine (25 mg/kg body wt, i.m., t.i.d.). After bile duct cannulation, 5 muCi of [6,7-3H]ethynylestradiol were injected i.v. and an 8-h bile collection was started. Bile flow in ethynylestradiol + S-adenosyl-L-methionine treated rats was similar to controls, but significantly higher than in ethynylestradiol-treated animals (1.44 +/- 0.11; 1.66 +/- 0.30; 0.97 +/- 0.17 microliter/min/g liver, respectively as mean +/- SE). Cholesterol molar percentage was significnatly higher in ethynylestradiol (3.46 +/- 0.25) than in ethynylestradiol + S-adenosyl-L-methionine treated (2.16 +/- 0.41) or control rats (1.90 +/- 0.30). Total radioactivity excretion was similar in all groups, ranging from 74% to 76% of the administered dose, but radiogaschromatography showed a significant increase of methylated ethynylestradiol metabolites in S-adenosyl-L-methionine treated rats. These data indicate that in ethynylestradiol treated rats S-adenosyl-L-methionine can: (a) reverse both cholestasis and related abnormalities of biliary lipids; (b) modify the pattern but not the total amount of biliary ethynylestradiol excretion.