C-Jun N-Terminal Kinase Modulates 1,25-Dihydroxyvitamin D3-Induced Cytochrome P450 3a4 Gene Expression

Abstract

Cytochrome P450 (P450) plays an important role in the oxidative metabolism of numerous endogenous and exogenous compounds. In humans, cytochrome P450 3A4 (CYP3A4) is the predominant P450 isoform in the liver and small intestinal epithelial cells (Watkins et al., 1987;Paine et al., 1997) and is responsible for the metabolism of more than 60% of therapeutic drugs. Intestinal CYP3A4 is thought to contribute to the first-pass metabolism of orally administered drugs . The CYP3A4 gene is inducible by many xenobiotics, including rifampicin, dexamethasone, and phenobarbital (Pichard et al., 1990). The nuclear receptor, pregnane X receptor, is known to contribute to the CYP3A4 gene induction by these drugs Lehmann et al., 1998;Goodwin et al., 1999). It has recently been demonstrated that 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) is a potent inducer of the CYP3A4 gene in the human colon carcinoma cell line Caco-2, which has been extensively used as an experimental model of small intestinal cells (Schmiedlin-Ren et al., 1997;Hara et al., 2000).1,25(OH) 2 D 3 , the most active metabolite of vitamin D, functions to regulate cellular proliferation and differentiation and calcium homeostasis in the intestine, bone, and kidney (Christakos et al., 1996). Most of these physiological activations are mediated by the vitamin D receptor (VDR), which belongs to the nuclear hormone receptor superfamily. The VDR acts as a ligand-inducible transcription factor through heterodimerization with the retinoid X receptor and binding to the vitamin D response element (VDRE) within the vitamin Dinducible genes (Christakos et al., 1996).Recently, a direct repeat separated by three nucleotides (DR3) and an everted repeat separated by six nucleotides (ER6) within the 5Ј-flanking region of the CYP3A4 gene were identified as VDRE (Thummel et al., 2001;Drocourt et al., 2002). We and others demonstrated that the VDR is an essential factor for 1,25(OH) 2 D 3 -induced CYP3A4 expression (Thummel et al., 2001;Drocourt et al., 2002;Hara et al., 2002). On the other hand, several reports have demonstrated that the phosphorylation step is critical for the expression of xenobiotic-induced P450 genes such as CYP1A1 and CYP3A (Chen and Tukey, 1996;Galisteo et al., 1999). We also showed that alteration of the cellular phosphorylation state mediated by protein kinase C (PKC) and protein tyrosine kinases affects the 1,25(OH) 2 D 3 -mediated induction of CYP3A4 mRNA in Caco-2 cells (Hara et al., 2002). In addition, the inhibition of the phosphorylation reduced the VDRmediated enhancement of osteocalcin gene transcription (Desai et al., 1995). These results suggest that the phosphorylation step is critical for the complete CYP3A4 induction by 1,25(OH) 2 D 3 via VDR. In the present study, we examined whether MAPKs are involved in the 1,25(OH) 2 D 3 -induced expression of the CYP3A4 gene via VDR. (Osaka, Japan). Curcumin was purchased from Nacalai Tesque (Kyoto, Japan). SB203580 was purchased from Calbiochem (San Diego, CA). SP600125 was synthesized as previously de...

Role of Vitamin D Receptor in the Lithocholic Acid-Mediated CYP3A Induction in Vitro and in Vivo

“…VD 3 was reported to induce CYP3A4 expression through the c-Jun NH 2 -terminal kinase pathway in Caco-2 cells (Yasunami et al, 2004). Therefore, LCA may be able to stimulate the c-Jun NH 2 -terminal kinase pathway as in the case of VD 3 .…”

Regulation of CYP24 splicing by 1,25-dihydroxyvitamin D3 in human colon cancer cells

“…Reports in the literature about the interaction between JNK and vitamin D do not support this concept. Yasunami et al (2004) demonstrated that SP600125 dose-dependently inhibited the CYP3A4 promoter activity induced by 1,25(OH) 2 D 3 ; however, SP600125 did not affect 1,25(OH) 2 D 3 -induced transactivation of the DR3 via VDR. Buitrago et al (2011) showed that 1,25(OH) 2 D 3 promotes the phosphorylation of JNK 1/2, the response was fast and maximal phosphorylation of the enzyme was observed at physiological doses of 1,25(OH) 2 D 3 .…”

Nuclear receptors: Genomic and non-genomic effects converge

“…[31][32][33][34][35] Also, 1,25(OH) 2 D 3 binds and activates PI3K in human THP-1 myeloid leukemia cells, which is required for the induction of CD14 and CD11b but not of p21 CIP1 . 36 However, these studies did not explain how the particular activation of one or more signaling enzymes might modulate gene regulation by the ligand.…”