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METABOLISM, TRANSPORT, AND PHARMACOGENOMICS

Induction of Human CYP2A6 Is Mediated by the Pregnane X Receptor with Peroxisome Proliferator-Activated Receptor- Coactivator 1

Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa, Japan (M.I., M.N., E.H., R.Y., T.Y.); and Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (K.N., Y.Y.)

CYP2A6 plays important roles in the metabolism of nicotine and some clinically used drugs. Interindividual variability in the CYP2A6 expression level in human liver might be caused by an inducible property, but the molecular mechanism of induction is unclear. Rifampicin, phenobarbital, and 6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde O-(3,4-dichlorobenzyl)oxime, which are activators of pregnane X receptor (PXR) and constitutive androstane receptor (CAR), induced CYP2A6 mRNA in human hepatocytes. We identified three direct repeat separated by four nucleotides (DR4)-like elements at –6698, –5476, and –4618 in the CYP2A6 gene, to which PXR and CAR could bind after dimerization with retinoid X receptor (RXR)-. In luciferase assays, overexpression of PXR or CAR could not activate the transcriptional activity of CYP2A6 promoter constructs (–6754 to –1) in HepG2 cells. Cotransfection of hepatocyte nuclear factor-4 did not affect the transcriptional activities in the absence or presence of PXR or CAR. Interestingly, cotransfection of peroxisome proliferator-activated receptor- coactivator 1 (PGC-1) as well as PXR significantly enhanced the transcriptional activity (3.9-fold of control). By the deletion of a possible suppresser region (–4533 to –185), the effects of PXR/PGC-1 on the transcriptional activity were increased (6.9-fold of control). Deletion or mutation analyses revealed that two DR4-like elements at –5476 and –4618 are essential for transactivation by PXR/PGC-1. Chromatin immunoprecipitation assay revealed that PXR and PGC-1 bind to CYP2A6 chromatin. In conclusion, we found that CYP2A6 is induced via PXR and PGC-1 through the DR4-like element at the distal response region. This is the first study to report the molecular mechanism of the induction of CYP2A6.

Address correspondence to: Dr. Miki Nakajima, Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192, Japan. E-mail: nmiki{at}kenroku.kanazawa-u.ac.jp

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				E. Higashi, T. Fukami, M. Itoh, S. Kyo, M. Inoue, T. Yokoi, and M. Nakajima Human CYP2A6 Is Induced by Estrogen via Estrogen Receptor Drug Metab. Dispos., October 1, 2007; 35(10): 1935 - 1941. [Abstract] [Full Text] [PDF]