Analysis of sex hormone-responsive element in sexually dimorphicly expressing CYP2B subfamily gene

• Project/Area Number: 10672105
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Environmental pharmacy
• Research Institution: TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY
• Principal Investigator: NEMOTO Nobuo TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY, Faculty of Pharmaceutical Sciences Professor, 薬学部, 教授 (10085631)
• Project Period (FY): 1998 – 2000
• Project Status: Completed (Fiscal Year 2000)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2000: ¥1,200,000 (Direct Cost: ¥1,200,000); Fiscal Year 1999: ¥1,100,000 (Direct Cost: ¥1,100,000); Fiscal Year 1998: ¥1,200,000 (Direct Cost: ¥1,200,000)
• Keywords: CYP2B / Sex hormone / Glucocorticoid hormone / Phenobarbital / 肝細胞初代培養系 / マウス肝細胞初代培養系

Research Abstract

CYP2B subfamily constitutively and sexually dimorphicly expresses in the liver. In the mouse, the expression in female is far higher than that in male and the expressed species are different between male (Crp2b10>Cyp2b9) and female (Cyp2b9>Cyp2b10). The expression of these species is inducible by phenobarbital (PB), and the induction mechanism has been extensively revealed at molecular level. However, the mechanism of their constitutive expression has been scarcely investigated.
Female and glucocorticoid hormones may participate the expression of Cyp2b9 and Cyp2b10, respecitively, and the latter hormone simultaneously suppresses Cyp2b9 expression. The role of male hormone is also considered to suppress Cyp2b9 expression. The sequence from -2331 to -2281 bp of the 5'-flanking region of Cyp2b10 gene is revealed to be responsible for the estradiol induction using luciferase assay. This region corresponds to the core element of PB-responsive enhancer module (PBREM). Several nucleotide mutations in the PBREM core element show that the NR1 (nuclear receptor 1) site is required for estradiol induction, the same element required for PB induction. The element also plays a critical role for induction by DDT, indicating that NR1 site responds to structurally-diversed inducers. Although Cyp2b9 is a major species expressed in female liver, no information is available for its expression mechanism, but estradiol is found as a potent inducer for investigating of the regulatory pathway.

Research Products

• [Publications] Sakuma T et al.: "Induction of CYP1A2 by phenobarbital in the livers of aryl hydrocarbon-responsive and -nonresponsive mice."Drug Metabol Dispos. 27巻. 379-384 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Miyamoto M et al.: "CYP2A6 gene deletion reduces susceptibility to lung cancer."Biochem Biophys Res Commun. 261巻. 658-660 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Jarukamjorn K et al.: "Different regulation of the expression of mouse hepatic cytochrome P4502B enzymes by glucocorticoid and phenobarbital."Arch Biochem Biophys. 369巻. 89-99 (1999)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sakuma T et al.: "A novel female-specific member of the CYP3A gene subfamily in the mouse liver."Arch Biochem Biophys. 377巻. 153-162 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Jarkumjorn K et al.: "Discriminating activation of CYP2B9 expression in male C57BL/6 mouse liver by β-estradiol."Biochem Biophys Res Commun. 279巻. 288-292 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Jarukamjorn K et al.: "Sex-associated expression of the mouse hepatic and renal CYP2B enzymes by glucocorticoid hormone."Biochem Pharmacol. (印刷中).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sakuma T et al.: "Induction of CYP1A2 by phenobarbital in the livers of aryl hydrocarbon-responsive and -nonresponsive mice."Drug Metabol Dispos. 27. 379-384 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Miyamoto M et al.: "CYP2A6 gene deletion reduces susceptibility to lung cancer."Biochem Biophys Res Commun. 261. 658-660 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Jarukamjorn K et al.: "Different regulation of the expression of mouse hepatic cytochrome P450 2B enzymes by glucocorticoid and phenobarbital."Arch Biochem Biophys. 369. 89-99 (1999)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sakuma T et al.: "A novel female-specific member of the CYP3A gene subfamily in the mouse liver."Arch Biochem Biophys. 377. 153-162 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Jarkumjorn K et al.: "Discriminating activation of CYP2B9 expression in male C57BL/6 mouse liver by β-estradiol."Biochem Biophys Res Commun. 279. 288-292 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Jarukamjorn K et al.: "Sex-associated expression of the mouse hepatic and renal CYP2B enzymes by glucocorticoid hormone."Biochem Pharmacol. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Sakuma T et al.: "A novel female-specific member of the CYP3A gene subfamily in the mouse liver."Arch Biochem Biophys. 377巻. 153-162 (2000)
• [Publications] Jarkumjorn K et al.: "Discriminating activation of CYP2B9 expression in male C57BL/6 mouse liver by β-estradiol."Biochem Biophys Res Commun. 279巻. 288-292 (2000)
• [Publications] Jarukamjorn K et al.: "Sex-associated expression of the mouse hepatic and renal CYP2B enzymes by glucocorticoid hormone."Biochem Pharmacol. (印刷中).
• [Publications] Yamamoto M et al.: "Localization of estradiol-responsive region in the phenobarbital-responsive enhancer module of mouse Cyp2b10 gene."J Biochem Mol Toxicol. (印刷中).
• [Publications] Sakuma T, Ohtake M, Katsurayama Y, Jarukamjorn K, Nemoto N.: "Induction of CYP1A2 by phenobarbital in the livers of aryl hydrocarbon-responsive and -nonresponsive mice."Drug Metabol Dispos. 27. 379-384 (1999)
• [Publications] Jarukamjorn K, Sakuma T, Miyaura J, Nemoto N.: "Different regulation of the expression of mouse hepatic cytochrome P450 2B enzymes by glucocorticoid and phenobarbital."Arch Biochem Biophys. 369. 89-99 (1999)
• [Publications] Miyamoto M, Umetsu Y, Dosaka-Akita H, Sawamura Y, Yokota J, Kunitoh H, Nemoto N, Sato K, Ariyoshi N, Kamataki T.: "CYP2A6 gene deletion reduces susceptibility to lung cancer."Biochem Biophys Res Commun. 261. 658-660 (1999)
• [Publications] Chida M, Yokoi T, Nemoto N, Inaba M, Kinoshita M, Kamataki T.: "A new variant CYP2D6 allele(CYP2D6^*21) with a single base insertion in exon 5 in Japanese population associated with a poor metabolizer phenotype."Pharmacogenetics. 9. 287-293 (1999)
• [Publications] Li H, Miyahara T, Tezuka Y, Namba T, Suzuki T, Dowaki R, Watanabe M, Nemoto N, Tonami S, Seto H, Kadota S.: "The effect of Kampo formulae on bone resorption in vitro and in vivo. II .Detailed study of berberine."Biol Pharm Bull. 22. 391-396 (1999)
• [Publications] Miyahara T, Harada M, Kozakai A, Matsumoto M, Hashimoto K, Inoue H, Yoda K, Nakatsu T, Kajita S, Yamazaki R, Higuchi S, Kozuka H, Nemoto N.: "Comparison of 26,27-hexafluoro-1α,25-dihydroxyvitamin D_3 and 1α,25-dihydroxyvitamin D_3 on the resorption of bone explants ex vivo."J Nur Sci Vitaminol. 45. 239-249 (1999)
• [Publications] Sakuma T,Ohtake M,Jarukamjorn K,Nemoto N: "Induction of CYPlA2 by phenobarbital in the livers of arylhydrocarbon-responsive and-nonresponsive mice." Drug Metabol.Dispo.In press.
• [Publications] Sakuma T,Hieda M,Ohgiya S,Nagata R,Nemoto N,Kamataki T: "Molecular cloning and functional analysis of cynomolgus monkey CYPIA2." Biochem.Pharmacol.56. 131-139 (1998)
• [Publications] Chida,M,Yokoi T,Nemoto N,Inaba M,Kinoshita M,Kamataki: "A new variant CYP2D6 allele(CYP2D6/C8)with a single base insertion in exon 5 in Japanese population associated with the poor metabolizer phenotype." Pharmacogenetics. in press.