Protein Information

ID 1844
Name Jun N terminal kinase (protein family or complex)
Synonyms c Jun N terminal kinase; JNK; c Jun NH (2) terminal kinase; Jun N terminal kinase

Compound Information

ID 868
Name sodium arsenite
CAS sodium arsenenite

Reference

PubMed Abstract RScore(About this table)
11408547 Vernhet L, Seite MP, Allain N, Guillouzo A, Fardel O: Arsenic induces expression of the multidrug resistance-associated protein 2 (MRP2) gene in primary rat and human hepatocytes. J Pharmacol Exp Ther. 2001 Jul;298(1):234-9.
Metals, such as arsenic or cadmium, have recently been demonstrated to interact with metabolic pathways, including phase I and phase II enzymes and the phase III efflux pump P-glycoprotein. In the present study, we investigated the effects of heavy metals and metalloids on the expression of the multidrug resistance-associated protein 2 (MRP2), a major hepatic transporter. Treatment of primary rat hepatocytes by sodium arsenite [As (III)], sodium arsenate and potassium antimony tartrate, but not cadmium chloride, was shown to markedly increase MRP2 mRNA and protein levels; As (III)-mediated induction was dose- and time-dependent and paralleled a strong increase in MRP2 amounts as assessed by Western blotting. As (III) was also demonstrated to markedly up-regulate MRP2 gene expression in primary human hepatocytes. MRP2 mRNA induction occurring in As (III)-treated rat hepatocytes was fully blocked by actinomycin D, indicating that it required active gene transcription. It was associated with an activation of the c-Jun N-terminal kinase pathway and with a reduction of cellular glutathione levels. Quercetin, a flavonoid compound known to block As (III)-related induction of P-glycoprotein, was also found to prevent up-regulation of MRP2 gene expression in rat hepatocytes 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 phosphorylation. It may rather be linked to the increase of cellular glutathione levels by quercetin, thus limiting the depleting effects of As (III) on glutathione amounts. Finally, these results confirm that some metals strongly regulate expression of detoxifying proteins, including biliary drug transporters.
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