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Drug Metabolism and Disposition Fast Forward
First published on March 22, 2006; DOI: 10.1124/dmd.106.009308

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Received for publication January 9, 2006.
Revised March 14, 2006.
Accepted for publication March 17, 2006.

Galactosamine prevents ethinylestradiol-induced cholestasis

Fernando A Crocenzi 1, Jose M Pellegrino 1, Viviana A Catania 1, Marcelo G Luquita 1, Marcelo G Roma 1, Aldo D Mottino 1, Enrique Sanchez Pozzi 1*

1 Instituto de Fisiologia Experimental

* Address correspondence to: E-mail: esanchez{at}agatha.unr.edu.ar

Abstract

Ethinylestradiol (EE) induces intrahepatic cholestasis in experimental animals, being its derivative ethinylestradiol 17{beta}-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 bw, s.c., for 5 consecutive days), the effect of simultaneous administration of galactosamine (200 mg/kg bw, 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-17{beta}-glucuronide after administration of a tracer dose of [3H]EE by 40%. Uridine (0.9 g/kg bw, i.p.) coadministration reverted the effect of galactosamine on hepatic UDP-GA levels and restored the excretion of [3H]EE-17{beta}-glucuronide. When administered for 5 days, galactosamine itself did not alter any of the serum markers of liver injury studied (AST, ALT, ALP) 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 17{beta}-glucuronide. The evidence thus supports the hypothesis that EE 17{beta}-glucuronide is involved in the pathogenesis of EE cholestasis.


Key words: glucuronidation, hepatobiliary transport, liver disease


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 Am. J. Physiol. Gastrointest. Liver Physiol.Home page
A. D. Mottino, T. Hoffman, F. A. Crocenzi, E. J. Sanchez Pozzi, M. G. Roma, and M. Vore
Disruption of function and localization of tight junctional structures and Mrp2 in sustained estradiol-17beta-D-glucuronide-induced cholestasis
Am J Physiol Gastrointest Liver Physiol, July 1, 2007; 293(1): G391 - G402.
[Abstract] [Full Text] [PDF]


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