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SHORT COMMUNICATION

C-JUN N-TERMINAL KINASE MODULATES 1,25-DIHYDROXYVITAMIN D₃-INDUCED CYTOCHROME P450 3A4 GENE EXPRESSION

Laboratory of Clinical Pharmaceutics (Y.Y., H.H., T.A.) and Department of Organic Chemistry (T.I., T.K.), Gifu Pharmaceutical University, Gifu, Japan

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) is known to induce the expression of cytochrome P450 3A4 (CYP3A4) in human colon carcinoma Caco-2 cells. Recently, it was demonstrated that the vitamin D receptor (VDR) regulates 1,25(OH)₂D₃-induced CYP3A4 gene expression through the xenobiotic-responsive element and the vitamin D-responsive element located on the 5'-flanking region of the CYP3A4 gene. On the other hand, we previously reported that protein kinases such as protein kinase C and tyrosine kinases contribute to the induction of CYP3A4 mRNA by 1,25(OH)₂D₃. In the present study, we examined the involvement of mitogen-activated protein kinases (MAPKs) in the 1,25(OH)₂D₃-induced CYP3A4 gene expression using MAPK inhibitors. Curcumin, a c-Jun N-terminal kinase (JNK) pathway inhibitor, and anthra[1,9-cd]pyrazole-6(2H)-one (SP600125), a JNK inhibitor, suppressed the induction of CYP3A4 mRNA by 1,25(OH)₂D₃, but not 2'-amino-3'-methoxyflavone (PD098059), a mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (ERK) pathway inhibitor, or 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580), a p38 inhibitor. In addition, we demonstrated that SP600125 dose-dependently inhibited the CYP3A4 promoter activity induced by 1,25(OH)₂D₃ using the reporter plasmid of the CYP3A4 promoter. However, SP600125 did not affect 1,25(OH)₂D₃-induced transactivation of the DR3 via VDR. These results indicate that JNK, but not ERK or p38, is required for the optimal activation of the CYP3A4 gene induced by 1,25(OH)₂D₃.

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