RT Journal Article
SR Electronic
T1 C-JUN N-TERMINAL KINASE MODULATES 1,25-DIHYDROXYVITAMIN D<sub>3</sub>-INDUCED CYTOCHROME P450 3A4 GENE EXPRESSION
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 685
OP 688
DO 10.1124/dmd.32.7.685
VO 32
IS 7
A1 Yoko Yasunami
A1 Hirokazu Hara
A1 Tatsunori Iwamura
A1 Tadashi Kataoka
A1 Tetsuo Adachi
YR 2004
UL http://dmd.aspetjournals.org/content/32/7/685.abstract
AB 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. The American Society for Pharmacology and Experimental Therapeutics