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

CATANIA VA; SÁNCHEZ POZZI EJ; LUQUITA MG; RUIZ ML; VILLANUEVA SSM; JONES B; MOTTINO AD

Annals of Hepatology

CONSORCIO EDITORIAL EL LEÓN DE SHALOM, S.A

Año: 2004 vol. 3 p. 11 - 17

Treatment of experimental animals with prototypicalenzyme inducers represents a useful tool to characterizethe role of different isozymes in drug metabolismand to improve our knowledge on factors regulatingtheir synthesis at the transcriptional level. The effectof model enzyme inducers on phase II (conjugating)enzyme families, including UDP-glucuronosyltransferase?sand glutathione-S-transferase?s, has been wellcharacterized in rodent liver. More recently, the effectof inducers on the expression of canalicular multidrugresistance-associated protein 2 (Mrp2) has been focusedupon. The identification of a number of conjugateddrugs as Mrp2 substrates suggests that both theconjugation and transport systems act coordinately toimprove drug elimination from the body. We provideevidence about circumstances resulting in the simultaneousupregulation of phase II enzymes and Mrp2 inhepatic and extrahepatic tissues, most likely involvingactivation of common nuclear receptors (e.g. FXR,PXR). Additionally, we provide an analysis of examplesof drug-induced toxicity leading to the simultaneousdownregulation of both systems. Potential therapeuticstrategies based on the modulation of expressionof these systems are also briefly commented upon.