ethinyl-estradiol-glucuronide and Cholestasis

Ethinylestradiol (EE) induces intrahepatic cholestasis in experimental animals being its derivative, ethinylestradiol 17beta-glucuronide, a presumed mediator of this effect. To test whether glucuronidation is a relevant step in the pathogenesis of cholestasis induced by EE (5 mg/kg b.wt. s.c. for 5 consecutive days), the effect of simultaneous administration of galactosamine (200 mg/kg b.wt. i.p.) on biliary secretory function was studied. A single injection of this same dose of galactosamine was able to decrease hepatic UDP-glucuronic acid (UDP-GA) levels by 85% and excretion of EE-17beta-glucuronide after administration of a tracer dose of [3H]EE by 40%. Uridine (0.9 g/kg b.wt. i.p.) coadministration reverted the effect of galactosamine on hepatic UDP-GA levels and restored the excretion of [3H]EE-17beta-glucuronide. When administered for 5 days, galactosamine itself did not alter any of the serum markers of liver injury studied (aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase) or biliary secretory function. When coadministered with EE, galactosamine partially prevented the impairment induced by this estrogen in total bile flow, the bile-salt-independent fraction of bile flow, basal bile salt secretion, and the secretory rate maximum of tauroursodeoxycholate. Uridine coadministration partially prevented galactosamine from exerting its anticholestatic effects. In conclusion, galactosamine administration partially prevented EE-induced cholestasis by a mechanism involving decreased UDP-GA availability for subsequent formation of EE 17beta-glucuronide. The evidence thus supports the hypothesis that EE 17beta-glucuronide is involved in the pathogenesis of EE cholestasis.

Topics: Animals; Bile; Cholestasis; Ethinyl Estradiol; Galactosamine; Liver; Male; Rats; Rats, Wistar; Taurochenodeoxycholic Acid; Uridine; Uridine Diphosphate Glucuronic Acid

The cholestasis induced by estrogen metabolites has been postulated to be due to an inhibition of bile acid transport. Therefore, the uptake of [3H]taurocholate (TC) into isolated hepatocytes was examined in the presence of known cholestatic steroid glucuronides. The cholestatic D-ring glucuronide conjugates of estradiol, estriol, ethynylestradiol and dihydrotestosterone did not inhibit the uptake of TC suggesting that these organic anions are transported by different carrier systems. Estrone sulfate inhibited TC uptake 65% but did not decrease bile flow following i.v. administration to the rat (22 mumol/kg), under conditions which the steroid glucuronide estradiol-17 beta-(beta-D-glucuronide) ( E217G ) decreased bile flow 100%. The hepatocytic uptake of [3H] E217G (100 microM) was inhibited by estriol-16 alpha-(beta-D-glucuronide) (200 microM, 40%) and estradiol-17 beta-3-(beta-D-glucuronide) (200 microM, 22%) as well as by the organic anions bromosulfophthalein (150 microM, 57%), dibromosulfophthalein (150 microM, 59%), indocyanine green (150 microM, 62%), rose bengal (150 microM, 56%) and bilirubin (50 microM, 40%). Thus, the bile acids and steroid glucuronides are transported into the hepatocyte by different carrier systems so that the cholestasis induced by the steroid D-ring glucuronides cannot be explained by an inhibition of bile acid uptake. Furthermore, the hepatocytic uptake of E217G occurs by a carrier system similar to that for the other steroid glucuronides and organic anions.

Topics: Animals; Cholestasis; Dihydrotestosterone; Estradiol; Estriol; Estrogens; Ethinyl Estradiol; Female; In Vitro Techniques; Liver; Rats; Rats, Inbred Strains; Taurocholic Acid

17 alpha-Ethynylestradiol-17 beta (beta-D-glucuronide) [EE217 beta (beta G)], a metabolite of 17 alpha-ethynylestradiol (EE2) identified in urine of women taking EE2 in oral contraceptives, and its synthetic anomer, 17 alpha-ethynylestradiol-17 beta (alpha-D-glucuronide), [EE217 beta (alpha G)], were administered intravenously to female rats in order to determine their effects on bile flow. Both agents induced an immediate, profound and dose-dependent decrease in bile flow which returned to control levels within 1-8 hr. The logarithm of the dose vs the cholestatic response curves for the two anomers were not parallel. EE217 beta (alpha G) was significantly more potent than EE217 beta (beta G) such that the doses inhibiting bile flow by 50% were 1.25 and 11 mumol/kg for the alpha-and beta-anomer respectively.

Topics: Animals; Bile; Cholestasis; Dose-Response Relationship, Drug; Ethinyl Estradiol; Female; Isomerism; Rats; Rats, Inbred Strains