Arsenic induces expression of the multidrug resistance-associated protein 2 (MRP2) gene in primary rat and human hepatocytes

Metals, such as arsenic or cadmium, have recently been demonstrated to inte ract with metabolic pathways, including phase I and phase II enzymes and th e phase III efflux pump P-glycoprotein. In the present study, we investigat ed the effects of heavy metals and metalloids on the expression of the mult idrug resistance-associated protein 2 (MRP2), a major hepatic transporter. Treatment of primary rat hepatocytes by sodium arsenite [As(III)], sodium a rsenate and potassium antimony tartrate, but not cadmium chloride, was show n to markedly increase MRP2 mRNA and protein levels; As(III)mediated induct ion was dose- and time-dependent and paralleled a strong increase in MRP2 a mounts as assessed by Western blotting. As(III) was also demonstrated to ma rkedly up-regulate MRP2 gene expression in primary human hepatocytes. MRP2 mRNA induction occurring in As(III)-treated rat hepatocytes was fully block ed by actinomycin D, indicating that it required active gene transcription. It was associated with an activation of the c-Jun N-terminal kinase pathwa y and with a reduction of cellular glutathione levels. Quercetin, a flavono id compound known to block As(III)related induction of P-glycoprotein, was also found to prevent up-regulation of MRP2 gene expression in rat hepatocy tes exposed to As(III), Such an effect was unlikely to be due to alteration of JNK pathway since quercetin failed to abolish As(III)-induced JNK phosp horylation. It may rather be linked to the increase of cellular glutathione levels by quercetin, thus limiting the depleting effects of As(III) on glu tathione amounts. Finally, these results confirm that some metals strongly regulate expression of detoxifying proteins, including biliary drug transpo rters.