孤儿核受体对尿苷二磷酸葡萄糖醛酸转移酶基因转录调节的研究进展

中国临床药理学与治疗学 ›› 2007, Vol. 12 ›› Issue (9): 974-979.

孤儿核受体对尿苷二磷酸葡萄糖醛酸转移酶基因转录调节的研究进展

张利, 周宏灏

中南大学临床药理研究所, 长沙410078, 湖南

收稿日期:2007-03-26 修回日期:2007-06-04 出版日期:2007-09-26 发布日期:2020-10-30
通讯作者: 周宏灏, 男, 院士, 从事临床药理学与遗传药理学研究。Tel:0731-4805379 E-mail:hhzhou2003@163.com
作者简介:张利, 女, 硕士在读, 研究方向为临床药理学与遗传药理学。Tel:13166020989 E-mail:forve@126.com

Advance in research of orphan nuclear receptor-mediated regulation of UDP-glucuronosyltransferases

ZHANG Li, ZHOU Hong-hao

Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China

Received:2007-03-26 Revised:2007-06-04 Online:2007-09-26 Published:2020-10-30

摘要/Abstract

摘要： 尿苷二磷酸葡萄糖醛酸转移酶(UDP-glucuronosyltransferase,UGT) 属于Ⅱ相药物代谢酶。它能催化葡醛酸与其相应底物结合, 是化学物质在生物体内进行Ⅱ相生物转化时最重要的一类酶。越来越多的研究发现, 孕烷X 受体(pregnane X receptor,PXR)、组成型雄甾烷受体(constitutive androstane receptor,CAR) 等孤儿核受体(orphan nuclear receptors)及其他转录因子能调节UGT 基因的转录, 这些受体及因子分布和活性的差异可导致UGT 酶表达和分布的差异。此外, 研究表明化合物通过核受体(NR)介导的UGT 酶表达量的变化可能是影响化合物体内代谢的一条重要途径。由于UGT 酶表达量与激素平衡、药物疗效、药物毒副作用及肿瘤等多种疾病发病预后密切相关, 所以研究核受体对Ⅱ相代谢酶的调节作用在预测药物相互作用、指导临床合理用药及人类疾病的预防等方面都具有重要意义。

关键词: 孤儿核受体, 基因调节, 尿苷二磷酸葡萄糖醛酸转移酶

Abstract: UDP-glucuronosyltransferases (UGTs) belong to the Phase II drug metabolizing enzymes.UGTs mediate transformations of glucuronic acid to xeno- and endobiotic chemicals, and it is the most important type of enzymes which involved in biotransformation of phase Ⅱ. More and more evidences have demonstrated that orphan nuclear receptors, such as pregnane X receptor (PXR), constitutive androstane receptor (CAR) and other transcriptional factors can regulate UGTs, differences of the factors above in distribution and activity can induce diversity of expression and activity of UGTs.Besides, researches indicated that the NR-mediated regulations of UGTs may contribute to variations of internal metabolism of compounds.In light of the expression of UGTs correlated to hormone homeostasis, therapeutic and side effects of medicine, incidence and prognosis of tumors and other diseases closely, therefore, elucidating UGT regulation by nuclear receptors has broad significance in drug interactions prediction and rational administration, human disease prevention and so on.

Key words: orphan nuclear receptor, gene regulation, UDP-glucuronosyltransferase

中图分类号:

R969
R968

张利, 周宏灏. 孤儿核受体对尿苷二磷酸葡萄糖醛酸转移酶基因转录调节的研究进展[J]. 中国临床药理学与治疗学, 2007, 12(9): 974-979.

ZHANG Li, ZHOU Hong-hao. Advance in research of orphan nuclear receptor-mediated regulation of UDP-glucuronosyltransferases[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2007, 12(9): 974-979.

参考文献

1 Mackenzie PI, Owens IS, Burchell B, et al.The UDP glycosy ltransferase gene superfamily :recommended nomenclature update based on evolutionary divergence [J].Pharmacogenetics, 1997;7:255-269.
2 Mackenziea PI, Bockb KW, Burchellc B, et al.Nomenclature update for the mammalian UDP-glycosyltransferase (UGT) gene superfamily [J].Pharmacogenet Genomics, 2005;15:677-685.
3 Lehmann JM, Mckee DD,Watson MA, et al.The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions [J].J Clin Invest, 1998;102:1016-1023.
4 Xu CJ, Christina Li YT, Ah-Ng TK.Induction of Phase I, II and III Drug Metabolism Transport by Xenobiotics [J].Arch Pharm Res, 2005;28:249-268.
5 Chambon P.A decade of molecular biology of retinoic acid receptors [J].FASEB J, 1996;10 :940-954.
6 Zhou J, Zhang J, Xie W.Xenobiotic nuclear receptor-mediated regulation of UDP-glucuronosy ltransferases [J].Curr Drug Metab, 2005;6:289-298.
7 Chinetti G, Lestavel S, Bocher V, et al.PPAR-[alpha] and PPAR-[gamma] activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway [J].Nat Med, 2001;7:53-58.
8 Chen C, Staudinger JL, Klaassen CD.Nuclear receptor, pregname X receptor, is required for induction of UDP-glucuronosyltranferases in mouse liver by pregnenolone-16 alpha-carbonitrile [J].Drug Metab Dispos, 2003;31:908-915.
9 Junko S, Shinichi N, Kasumi Y, et al.Transcriptional regulation of human UGT1A1 gene expression:activated glucocorticoid receptor enhances constitutive androstane receptor pregnane X receptor-mediated UDP-glucuronosyltransferase 1A1 regulation with glucocorticoid receptor-interacting protein 1 [J].Mol Pharmacol, 2005;67:845-855.
10 Shelby MK, Klaassen CD.Induction of rat UDP-glucuronosyltransferases in liver and duodenum by microsomal enzyme inducers that activate various transcriptional pathways [J].Drug Metab Dispos, 2006;34:1772-1778.
11 Usui T, Kuno T, Mizutani T.Induction of human UDP-glucuronosyltransferase 1A1 by cortisol-GR [J].Mol Biol Rep, 2006;33:91-96.
12 Gardner-Stephen D, Heydel JM, GoyalA, et al.Human PXR variants and their differential effects on the regulation of human UDP-glucuronosyltransferase gene expression [J].Drug Metab Dispos, 2004;32 :340-347.
13 Heydel J, Leclerc S, Bernard P, et al.Rat olfactory bulb and epithelium UDP-glucuronosyltransferase 2A1 (UGT2A1) expression: in situ mRNA localization and quantitative analy sis [J].Brain Res Mol Brain Res, 2001;90 :83-92.
14 Junko S, Tatsuy a S, Masahiko N, et al.Regulation of the human UGT1A1 gene by nuclear receptors constitutive active androstane receptor, pregnane x receptor, and glucocorticoid receptor [J].Methods Enzymol, 2005;400:92-104.
15 Barbier O, Villeneuve L, Bocher V, et al.The UDP-glucuronosyltransferase 1A9 enzyme is a peroxisome proliferator-activated receptor αand γtarget gene [J].J Biol Chem, 2003;278 : 13975-13983.
16 Barbier O, Duran-Sandoval D, Pineda-Torra I, et al.Peroxisome proliferator-activated receptor αinduces hepatic expression of the human bile acid glucuronidating UDP-glucuronosyltransferase 2B4 enzyme [J].J Biol Chem, 2003;278 :32852-32860.
17 Emi Y, Ikushiro S, Iyanagi T.Drug-responsive and tissue-specific alternative expression of multiple first exons in rat UDPglucuronosyltransferase family 1 (UGT1) gene complex [J].J Biochem, 1995;117:392-399.
18 Cereghini S, Blumenfeld M, Yaniv M.A liver-specific factor essential for albumin transcription differs between differentiated and dedifferentiated rat hepatoma cells [J].Genes Dev, 1998; 2 :957-974.
19 Cummins CL, Mangelsdorf DJ.Liver X receptors and cholesterol homoeostasis:spotlight on the adrenal gland [J].Biochem Soc Trans, 2006;34 :1110-1113.
20 Cha JY, Repa JJ.The liver X receptor (LXR) and hepatic lipogenesis, the carbohydrate-response element-binding protein is a target gene of LXR [J].J Biol Chem, 2007;282:743-751.
21 Wente W, Brenner MB, Zitzer H, et al.Activation of liver X receptors and retinoid X receptors induces growth arrest and apoptosis in insulin-secreting cells [J].Endocrinology, 2007; 148:1843-1849.
22 Kast HR, Goodwon B, Tarr PT, et al.Regulation of multidrug resistance-associated protein 2 (ABCC2) by the nuclear receptors pregnane X receptor, farnesoid X-activated receptor, and consititutive androstane receptor [J].J Biol Chem, 2002;277: 2908-2915.
23 Verreault M, Senekeo-Effenberger K, Trottier J, et al.The liver X-receptor alpha controls hepatic expression of the human bile acid-glucuronidating UGT1A3 enzyme in human cells and transgenic mice [J].Hepatology, 2006;44:368-378.
24 Lu Y, Heydel JM, Li X, et al.Lithocholic acid decreases expression of UGT2B7 in Caco-2 cells :a potential role for a negative farnesoid X receptor response element [J].Drug Metab Dispos, 2005;33:937-946.
25 Senekeo-Effenberger K, Chen S, Brace-Sinnokrak E, et al. Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2, 3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation [J].Drug Metab Dispos, 2007;35:419-427.
26 Ishii Y, Hansen AJ, Mackenzie PI, et al.Octamer transcription factor-1 enhances hepatic nuclear factor-1a-mediated activation of the human UDP-glucuronosyltransferase 2B7 promoter [J].Mol pharmacol, 2000;57 :940-947.
27 Bernard P, Goudonnet H, Artur Y, et al.Activation of the mouse TATA-less and human TATAcontaining UDP-glucuronosyltransferase 1A1 promoters by hepatocyte nuclear factor 1 [J]. Mol Pharmacol, 1999;56:526-536.
28 Gregory PA, Lewinsky RH, Gardner-Stephen DA, et al.Coordinate regulation of the human UDP-glucuronosyltransferase A8, 1A9, and 1A10 genes by epatocyte nuclear factor 1 and the caudal-related homeodomain protein 2 [J].Mol Pharmacol, 2004;65:953-963.
29 Gregory PA, Mackenzie PI.The homeodomain Pbx2-Prep1 complex modulates hepatocyte nuclear factor 1-mediated activation of the UDP-glucuronosyltransferase 2B17 gene [J].Mol Pharmacol, 2002;62 :154-161.
30 Yang XY, Zhao WP, Li YQ, et al.The role of NF-E2-related factor 2 in the induction of uridine 5'-diphosphate-glucuronosyltransferase 1A and its isoforms by epigallocatechin gallate in colon cancer cells [J].Zhonghua Yi Xue Za Zhi, 2006;86 :82-87.