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Drug Metabolism and Disposition Fast Forward
First published on July 23, 2007; DOI: 10.1124/dmd.107.016568

0090-9556/07/3510-1935-1941$20.00
DMD 35:1935-1941, 2007

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Human CYP2A6 Is Induced by Estrogen via Estrogen Receptor

Eriko Higashi, Tatsuki Fukami, Masahiro Itoh, Satoru Kyo, Masaki Inoue, Tsuyoshi Yokoi, and Miki Nakajima

Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences (E.H., T.F., M.It., T.Y., M.N.), and Department of Obstetrics and Gynecology (S.K., M.In.), Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa, Japan

Human CYP2A6, which is predominantly expressed in liver, is a key enzyme responsible for the metabolism of nicotine, coumarin, and some pharmaceutical drugs. CYP2A6 is also expressed in sex steroid-responsive tissues such as breast, ovary, uterus, testis, and adrenal grand. In this study, we examined the regulation of CYP2A6 gene by estrogen. Reverse transcription-polymerase chain reaction (RT-PCR) assays revealed that CYP2A6 mRNA was induced by estradiol in estrogen receptor (ER)-positive MCF-7 (2.9-fold) and HepG2 (1.3-fold) cells, but not in ER-negative MDA-MB-435 cells. Real-time RT-PCR assays revealed the CYP2A6 induction by estradiol in human hepatocytes (1.2- to 1.5-fold). Computer-assisted homology search identified a putative estrogen response element (ERE) at -2436 on the CYP2A6 gene. Electrophoretic mobility shift assays demonstrated specific binding of ER{alpha} to this element. Luciferase assays using MCF-7 cells revealed that the transcriptional activity of the CYP2A6 promoter was significantly activated by estradiol in an ER{alpha}-dependent manner, in which ERE was responsible for the activation. Chromatin immunoprecipitation assays verified the in vivo association of ER{alpha} with the ERE on the CYP2A6 gene. Immunohistochemical analyses using human endometrial tissues indicated that the CYP2A6 protein level in glandular cells was significantly higher in the proliferative phase than in the secretory phase, concomitant with local estrogen secretion during the menstrual cycle. These findings clearly demonstrated that CYP2A6 is directly induced by estrogen in an ER{alpha}-dependent manner, implying a biological role of CYP2A6 in estrogen-responsive tissues. Furthermore, this mechanism can also explain clinical aspects of increased nicotine metabolism under estrogen-rich environments.

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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