Galactosamine prevents ethinylestradiol-induced 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.
Instituto de Fisiología Experimental, Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario. Suipacha 570 (2000) Rosario, Argentina.
Fernando A
FA
Crocenzi
José M
JM
Pellegrino
Viviana A
VA
Catania
Marcelo G
MG
Luquita
Marcelo G
MG
Roma
Aldo D
AD
Mottino
Enrique J Sánchez
EJ
Pozzi
D000818:Animals; D001646:Bile / Q000737:chemistry / Q000187:drug effects* / Q000502:physiology; D002779:Cholestasis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism / Q000633:toxicity; D005688:Galactosamine / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013655:Taurochenodeoxycholic Acid / Q000378:metabolism; D014529:Uridine / Q000494:pharmacology; D014535:Uridine Diphosphate Glucuronic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism
C024860:ethinyl estradiol glucuronide; D014535:Uridine Diphosphate Glucuronic Acid; D004997:Ethinyl Estradiol; D013655:Taurochenodeoxycholic Acid; C031655:ursodoxicoltaurine; D005688:Galactosamine; D014529:Uridine