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J. Biol. Chem., Vol. 278, Issue 38, 36328-36333, September 19, 2003

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Rapid Stimulation of Free Glucuronate Formation by Non-glucuronidable Xenobiotics in Isolated Rat Hepatocytes^*

Carole L. Linster  and Emile Van Schaftingen 

From the Laboratory of Physiological Chemistry, Université de Louvain and the Christian de Duve Institute of Cellular Pathology, B-1200 Brussels, Belgium

Vitamin C synthesis in rat liver is enhanced by several xenobiotics, including aminopyrine and chloretone. The effect of these agents has been linked to induction of enzymes potentially involved in the formation of glucuronate, a precursor of vitamin C. Using isolated rat hepatocytes as a model, we show that a series of agents (aminopyrine, antipyrine, chloretone, clotrimazole, metyrapone, proadifen, and barbital) induced in a few minutes an up to 15-fold increase in the formation of glucuronate, which was best observed in the presence of sorbinil, an inhibitor of glucuronate reductase. They also caused an 2-fold decrease in the concentration of UDP-glucuronate but little if any change in the concentration of UDP-glucose. Depletion of UDP-glucuronate with resorcinol or D-galactosamine markedly decreased the formation of glucuronate both in the presence and in the absence of aminopyrine, confirming the precursor-product relationship between UDP-glucuronate and free glucuronate. Most of the agents did not induce the formation of detectable amounts of glucuronides, indicating that the formation of glucuronate is not due to a glucuronidation-deglucuronidation cycle. With the exception of barbital (which inhibits glucuronate reductase), all of the above mentioned agents also caused an increase in the concentration of ascorbic acid. They had little effect on glutathione concentration, and their effect on glucuronate and vitamin C formation was not mimicked by glutathione-depleting agents such as diamide and buthionine sulfoximine. It is concluded that the stimulation of vitamin C synthesis exerted by some xenobiotics is mediated through a rapid increase in the conversion of UDP-glucuronate to glucuronate, which does not apparently involve a glucuronidation-deglucuronidation cycle.

Received for publication, June 20, 2003 , and in revised form, July 11, 2003.

^* This work was supported by the Concerted Research Action Program of the Communauté Française de Belgique, the Belgian Federal Service for Scientific, Technical, and Cultural Affairs, and the Fonds de la Recherche Scientifique Médicale. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

A fellow of the Fonds National de la Recherche Scientifique.

To whom correspondence should be addressed. Tel.: 32-2-7647564; Fax: 32-2-7647598; E-mail address: vanschaftingen{at}bchm.ucl.ac.be.

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