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A Common Regulatory Region Functions Bidirectionally in Transcriptional Activation of the Human CYP1A1 and CYP1A2 Genes

Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan (R.U., H.I., K.N., Y.Y.); Comprehensive Research and Education Center for Planning of Drug Development and Clinical Evaluation, Tohoku University 21st Century "Center of Excellence" Program (Y.Y.), Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, Maryland (S.K., F.J.G.); and Drug Metabolism and Pharmacokinetics Research, Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba, Japan (R.U., K.K., T.Y.)

The human CYP1A1 and CYP1A2 genes on chromosome 15 are orientated head-to-head and are separated by a 23-kilobase (kb) intergenic spacer region. Thus, the possibility exists for sharing common regulatory elements contained in the spacer region responsible for transcriptional activation and regulation of the CYP1A1 and CYP1A2 genes. In the present study, a reporter gene construct containing -22.4 kb of the 5'-flanking region of the CYP1A2 gene was found to support -naphthoflavone (BNF) and 3-methylchoranthrene (3-MC)-mediated transcriptional activation. The responsive region was also functional in directing activation of the CYP1A1 promoter, indicating that the region works bidirectionally to govern transcriptional activation of both CYP1A1 and CYP1A2. To simultaneously evaluate transcriptional activation of both genes, a dual reporter vector was developed in which the spacer region was inserted between two different reporter genes, firefly luciferase and secreted alkaline phosphatase. Transient transfection of the dual reporter vector in HepG2 cells revealed increases in both reporter activities after exposure of the cells to BNF and 3-MC. Deletion studies of the spacer region indicated that a region from -464 to -1829 of the CYP1A1 gene works bidirectionally to enhance the transcriptional activation of not only CYP1A1 but also CYP1A2. In addition, a negative bidirectional regulatory region was found to exist from -18,989 to -21,992 of the CYP1A1 gene. These data established that induction of human CYP1A1 and CYP1A2 is simultaneously controlled through bidirectional and common regulatory elements.

Address correspondence to: Dr. Kiyoshi Nagata, Division of Drug Metabolism and Molecular Toxicology, Graduate School of Pharmaceutical Sciences, Tohoku University, Aramaki-Aoba 6-3, Aoba-ku, Sendai, 980-8578, Japan. E-mail: nagataki{at}mail.tains.tohoku.ac.jp

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