药学学报, 2017, 52(1): 44-50
引用本文:
韩坤, 陆思洁, 曾苏, 余露山. 佐米曲坦诱导雄性大鼠肝CYP3A2的作用机制[J]. 药学学报, 2017, 52(1): 44-50.
HAN Kun, LU Si-jie, ZENG Su, YU Lu-shan. Induction study of CYP3A2 in male rats by zolmitriptan[J]. Acta Pharmaceutica Sinica, 2017, 52(1): 44-50.

佐米曲坦诱导雄性大鼠肝CYP3A2的作用机制
韩坤, 陆思洁, 曾苏, 余露山
浙江大学药学院药物代谢和药物分析研究所, 浙江省抗肿瘤药物研究重点实验室, 浙江 杭州 310058
摘要:
作者前期研究发现佐米曲坦(ZOL)对雄性大鼠肝中CYP3A2具有诱导作用,而对雌性大鼠没有诱导作用。阐明其机制对于研究ZOL的药物相互作用和个体化用药具有积极意义。由于生长激素(GH)与一些蛋白的性别差异性表达密切相关,因此,本研究探究了ZOL对大鼠GH分泌的影响,以及其对脑垂体化学损伤大鼠模型肝中CYP3A2的诱导作用。结果发现,ZOL可以抑制正常大鼠体内血浆GH水平。与正常组大鼠的诱导结果不同,ZOL抑制了损伤组雄性大鼠肝中CYP3A2的表达。另外,ZOL对于雌雄原代肝细胞中的CYP3A1/2无明显诱导作用。进一步研究发现,给予ZOL后正常雄性大鼠肝中肝细胞核因子4α(HNF4α)的入核水平明显增加,而正常雌性大鼠、脑垂体化学损伤大鼠和大鼠原代肝细胞中HNF4α的入核水平无明显变化。结果表明,GH和HNF4α在ZOL性别差异性诱导CYP3A2的过程中发挥了重要的作用。
关键词:    佐米曲坦      CYP3A2      性别选择性诱导      生长激素      肝细胞核因子4α     
Induction study of CYP3A2 in male rats by zolmitriptan
HAN Kun, LU Si-jie, ZENG Su, YU Lu-shan
Institute of Drug Metabolism and Pharmaceutical Analysis, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
Abstract:
In our preliminary studies, we observed zolmitriptan (ZOL) treatment led to induction of CYP3A2 in male not female rats. To figure out the reason is of great significance for drug-drug interactions and personalized administration. Since growth hormone (GH) is known as the major mechanistic determinant of sexually-dimorphic gene expression like CYP3A2 in rat liver, the impacts of ZOL on both plasma GH levels in non monosodium glutamate (MSG)-treated rats and CYP3A2 expression in GH depleted MSG-treated rats were studied. ZOL was shown to partially suppress GH levels in both genders. Furthermore, CYP3A2 protein and mRNA level declined in male not female MSG-treated rats. In order to study the possible molecular events involved in the depression of GH and gender-selective induction on rat CYP3A2 by ZOL, the mRNA and protein level (whole protein and nuclear protein) of hepatocyte nuclear factor 4α (HNF4α) was investigated. Nuclear accumulation of HNF4α was observed in the normal male not female rat liver tissue following ZOL treatment. However, this kind of nuclear translocation did not occur in rat hepatocytes and MSG-treated rats. These findings demonstrated CYP3A2 inducibility by ZOL was gender-selective. GH and HNF4α may play an important role in CYP3A2 induction.
Key words:    zolmitriptan    CYP3A2    gender-dependent induction    growth hormone    hepatocyte nuclear factor 4α   
收稿日期: 2016-10-17
DOI: 10.16438/j.0513-4870.2016-1007
基金项目: 国家自然科学基金资助项目(30600772).
通讯作者: 余露山,Tel:86-571-88208407,E-mail:yuls@zju.edu.cn
Email: yuls@zju.edu.cn
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参考文献:
[1] Lionetto L, Casolla B, Mastropietri F, et al. Pharmacokinetic evaluation of zolmitriptan for the treatment of migraines[J]. Expert Opin Drug Metab Toxicol, 2012, 8:1043-1050.
[2] Srinivas NR, Syed M. Intranasal pharmacokinetic data for triptans such as sumatriptan and zolmitriptan can render area under the curve (AUC) predictions for the oral route:strategy development and application[J]. J Pain Palliat Care Pharmacother, 2016, 30:13-24.
[3] King CD, Rios GR, Green MD, et al. UDP-Glucuronosyltransferases[J]. Curr Drug Metab, 2000, 1:143-161.
[4] Bjornsson TD, Callaghan JT. Perspective the conduct of in vitro and in vivo drug-drug interaction studies:a pharmaceutical research and manufacturers of America (PhRMA) perspective[J]. Drug Metab Dispos, 2003, 31:815-832.
[5] Kaiser N, Nesher R, Oprescu A, et al. Characterization of the action of S 21403(mitiglinide) on insulin secretion and biosynthesis in normal and diabetic beta-cells[J]. Br J Pharmacol, 2005, 146:872-881.
[6] Yu LS, Zeng S. Determination of mitiglinide in rat plasma by high-performance liquid chromatography with UV detection[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2006, 834:204-207.
[7] Yu LS, Lu SJ, Zhao NP, et al. Male-specific induction of CYP3A2 in rats by zolmitriptan[J]. J Pharm Pharmacol, 2008, 60:1601-1607.
[8] Thangavel C, Boopathi E, Shapiro BH. Intrinsic sexually dimorphic expression of the principal human CYP3A4 correlated with suboptimal activation of GH/glucocorticoid-dependent transcriptional pathways in men[J]. Endocrinology, 2011, 152:4813-4824.
[9] Shapiro BH, Agrawal AK, Pampori NA. Gender differences in drug metabolism regulated by growth hormone[J]. Int J Biochem Cell Biol, 1995, 27:9-20.
[10] Pampori NA, Shapiro BH. Gender differences in the responsiveness of the sex-dependent isoforms of hepatic P450 to the feminine plasma growth hormone profile[J]. Endocrinology, 1999, 140:1245-1254.
[11] Li J, Wan Y, Na S, et al. Sex-dependent regulation of hepatic CYP3A by growth hormone:roles of HNF6, C/EBPα and RXRα[J]. Biochem Pharmacol, 2015, 93:92-103.
[12] Banerjee S, Das RK, Shapiro BH. Growth hormoneindependent suppression of growth hormone-dependent female isoforms of cytochrome P450 by the somatostatin analog octreotide[J]. Eur J Pharmacol, 2013, 715:256-261.
[13] Das RK, Banerjee S, Shapiro BH. Noncanonical suppression of GH-dependent isoforms of cytochrome P450 by the somatostatin analog octreotide[J]. J Endocrinol, 2013, 216:87-97.
[14] Kaji H, Kume T. Regioselective glucuronidation of denopamine:marked species differences and identification of human UDP-glucuronosyltransferase isoform[J]. Drug Metab Dispos, 2005, 33:403-412.
[15] Ritter JK, Chen F, Sheen YY, et al. A novel complex locus UGT1 encodes human bilirubin, phenol, and other UDP-glucuronosyltransferase isozymes with identical carboxyl termini[J]. J Biol Chem, 1992, 267:3257-3261.
[16] Miners JO, Mackenzie PI. Drug glucuronidation in humans[J]. Pharmacol Ther, 1991, 51:347-369.
[17] Thangavel C, Boopathi E, Shapiro BH. Inherent sexdependent regulation of human hepatic CYP3A5[J]. Br J Pharmacol, 2013, 168:988-1000.
[18] Harding D, Fournel-Gigleux S, Jackson MR, et al. Cloning and substrate specificity of a human phenol UDP-glucuronosyltransferase expressed in COS-7 cells[J]. Proc Natl Acad Sci U S A, 1988, 85:8381-8385.
[19] Jin CJ, Miners JO, Lilywhite KL, et al. cDNA cloning and expression of two new members of the human liver UDPglucuronosyltransferase 2B subfamily[J]. Biochem Biophys Res Commun, 1993, 194:496-503.
[20] Pampori NA, Shapiro BH. Feminization of hepatic cytochrome P450s by nominal levels of growth hormone in the feminine plasma profile[J]. Mol Pharmacol, 1996, 50:1148-1156.
[21] Berry MN, Friend DS. High-yield preparation of isolated rat liver parenchymal cells:a biochemical and fine structural study[J]. J Cell Biol, 1969, 43:506-520.
[22] Pampori NA, Agrawal AK, Waxman DJ, et al. Differential effects of neonatally administered glutamate on the ultradian pattern of circulating growth hormone regulating expression of sex-dependent forms of cytochrome P450[J]. Biochem Pharmacol, 1991, 41:1299-1309.
[23] Ahluwalia A, Clodfelter KH, Waxman DJ. Sexual dimorphism of rat liver gene expression:regulatory role of growth hormone revealed by deoxyribonucleic acid microarray analysis[J]. Mol Endocrinol, 2004, 18:747-760.
[24] Colby HD, Gaskin JH, Kitay JI. Requirement of the pituitary gland for gonadal hormone effects on hepatic corticosteroid metabolism in rats and hamsters[J]. Endocrinology, 1973, 92:769-774.
[25] Denef C. Effect of hypophysectomy and pituitary implants at puberty on the sexual differentiation of testosterone metabolism in rat liver[J]. Endocrinology, 1974, 94:1577-1582.
[26] Gustafsson JA, Stenberg A. Masculinization of rat liver enzyme activities following hypophysectomy[J]. Endocrinology, 1974, 95:891-896.
[27] Maruyama M, Fujisawa M, Yokosuka M, et al. A new in vivo analysis model to detect sexually dimorphic rat liver cytochrome P450 gene expression dependent on growth hormone secretory patterns[J]. Exp Anim, 2016, 65:447-454.
[28] Martin GR. Pre-clinical pharmacology of zolmitriptan (Zomig; formerly 311C90), a centrally and peripherally acting 5HT1B/1D agonist for migraine[J]. Cephalgia, 1997, 17:4-14.
[29] Agrawal AK, Shapiro BH. Differential expression of genderdependent hepatic isoforms of cytochrome P-450 by pulse signals in the circulating masculine episodic growth hormone profile of the rat[J]. J Pharmacol Exp Ther, 2000, 292:228-237.
[30] Hemeryck A, Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P-450 mediate drug-drug interactions:an update[J]. Curr Drug Metab, 2002, 3:13-37.
[31] Probst-Schendzielorz K, Viviani R, Stingl JC. Effect of cytochrome P450 polymorphism on the action and metabolism of selective serotonin reuptake inhibitors[J]. Expert Opin Drug Metab Toxicol, 2015, 11:1219-1232.
[32] Hirsh-Rokach B, Spectre G, Shai E, et al. Differential impact of selective serotonin reuptake inhibitors on platelet response to clopidogrel:a randomized, double-blind crossover trial[J]. Pharmacotherapy, 2015, 35:140-147.
[33] Wiwi CA, Gupte M, Waxman DJ. Sexually dimorphic P450 gene expression in liver-specific hepatocyte nuclear factor 4alphadeficient mice[J]. Mol Endocrinol, 2004, 18:1975-1987.
[34] Wiwi CA, Waxman DJ. Role of hepatocyte nuclear factors in transcriptional regulation of male-specific CYP2A2[J]. J Biol Chem, 2005, 280:3259-3268.
[35] Wiwi CA, Waxman DJ. Role of hepatocyte nuclear factors in growth hormone-regulated, sexually dimorphic expression of liver cytochromes P450[J]. Growth Factors, 2004, 22:79-88.
[36] Park SH, Waxman DJ. Inhibitory cross-talk between STAT5b and liver nuclear factor HNF3beta:impact on the regulation of growth hormone pulse-stimulated, male-specific liver cytochrome P-450 gene expression[J]. J Biol Chem, 2001, 276:43031-43039.
[37] Thunell S. (Far) Outside the box:genomic approach to acute porphyria[J]. Physiol Res, 2006, 55:S43-S66.