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Co-regulation of expression of phase II metabolizing enzymes and multidrug resistance-associated protein 2

Viviana A. Catania, Enrique J. Sánchez Pozzi, Marcelo G. Luquita, María L. Ruiz, Silvina S.M. Villanueva, Brett Jones, Aldo D. Mottino

Abstract

Treatment of experimental animals with prototypical enzyme inducers represents a useful tool to characterize the role of different isozymes in drug metabolism and to improve our knowledge on factors regulating their synthesis at the transcriptional level. The effect of model enzyme inducers on phase II (conjugating) enzyme families, including UDP-glucuronosyltransferase’s and glutathione-S-transferase’s, has been well characterized in rodent liver. More recently, the effect of inducers on the expression of canalicular multidrug resistance-associated protein 2 (Mrp2) has been focused upon. The identification of a number of conjugated drugs as Mrp2 substrates suggests that both the conjugation and transport systems act coordinately to improve drug elimination from the body. We provide evidence about circumstances resulting in the simultaneous upregulation of phase II enzymes and Mrp2 in hepatic and extrahepatic tissues, most likely involving activation of common nuclear receptors (e.g. FXR, PXR). Additionally, we provide an analysis of examples of drug-induced toxicity leading to the simultaneous downregulation of both systems. Potential therapeutic strategies based on the modulation of expression of these systems are also briefly commented upon.

Key words. UDP-glucuronosyltransferase, glutathione- S-transferase, protein induction, cholestasis, nuclear receptors

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The Official Journal of the Mexican Association of Hepatology, the Latin-American Association for the Study of the Liver and the Canadian Association for the Study of the Liver

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