Rapid and drastic induction of CYP3A4 mRNA expression via vitamin D receptor in human intestinal LS180 cells.
The aim of this study was to evaluate the usefulness of human intestinal LS180 cells for studying the induction of CYP3A4 mRNA expression via vitamin D receptor (VDR). CYP3A4 mRNA expression in LS180 cells treated with 100 nM 1alpha,25-dihydroxyvitamin D(3) (1alpha,25(OH)(2)D(3)) for 6 and 24 h was approximately 80- and 500-fold higher than the control, respectively. A protein kinase (PK) inhibitor (staurosporine), c-jun N-terminal kinase (JNK) pathway inhibitor (curcumin), and JNK inhibitor (SP600125) attenuated 1alpha,25(OH)(2)D(3)-induced CYP3A4 mRNA expression, suggesting that the PK-JNK pathway contributed to the rapid and drastic induction of CYP3A4 expression via VDR in LS180 cells. The ability of CYP3A4 mRNA induction in LS180 cells was highly dependent on the site and number of vitamin D(3) and D(2) hydroxylation. In addition, short-time (6 h) treatment of LS180 cells with cytotoxic secondary bile acids, lithocholic acid (LCA) and 3-keto-LCA also significantly induced the mRNA expression of CYP3A4. LS180 cells may be useful to quickly investigate the CYP3A4-inducing effect of drugs, xenobiotics, and/or endogenous substrates in the intestinal epithelia.
Fukumori
Shiro
S
Graduate School of Pharmaceutical Sciences, University of Toyama, Toyoma, Japan.
Murata
Toshiya
T
Taguchi
Masato
M
Hashimoto
Yukiya
Y
D000873:Anthracenes / Q000494:pharmacology; D002117:Calcitriol / Q000378:metabolism; D002460:Cell Line; D003474:Curcumin / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D004790:Enzyme Induction; D006801:Humans; D006900:Hydroxylation; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D008095:Lithocholic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis*; D018167:Receptors, Calcitriol / Q000378:metabolism*; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*
C455860:3-ketolithocholic acid; D000873:Anthracenes; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014807:Vitamin D; C432165:pyrazolanthrone; D008095:Lithocholic Acid; D003577:Cytochrome P-450 Enzyme System; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D002117:Calcitriol; D019311:Staurosporine; D003474:Curcumin