[1]何 航,阚全程,张莉蓉.药物代谢酶的个体发育及表观遗传调控[J].中国药理学通报,2017,(02):167-171.[doi:10.3969/j.issn.1001-1978.2017.02.005]
 HE Hang,KAN Quan-cheng,ZHANG Li-rong.Ontogeny of drug metabolism enzymes and epigentic regulation[J].Chinese Pharmacological Bulletin,2017,(02):167-171.[doi:10.3969/j.issn.1001-1978.2017.02.005]





Ontogeny of drug metabolism enzymes and epigentic regulation
何 航13阚全程2张莉蓉1
1.郑州大学基础医学院药理学系,河南 郑州 450001;
2.郑州大学第一附属医院, 河南 郑州 450052;
3.河南中医药大学细胞免疫病原学教研室,河南 郑州 450046
HE Hang13 KAN Quan-cheng2 ZHANG Li-rong1
1.Dept of Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001,China;
2.the First Affiliated Hospital, Zhengzhou University, Zhengzhou 450052,China;
3.Dept of Immunology and Etiology, Henan University of Traditional Chinese Medicine, Zhengzhou 450046,China
个体发育 药物代谢酶 表观遗传学 发育开关 组蛋白甲基化 核受体
ontogeny DME epigenetics developmental switch histone methylation nuclear receptor
在个体发育过程中,药物代谢酶(drug metabolizing enzyme,DME)的表达发生明显变化,根据个体发育特点分为3类:第一类酶在妊娠前3个月胎儿表达水平高,至妊娠末仍然保持高水平或略微下降,出生后1~2 年表达水平则明显降低。第二类酶在妊娠期表达水平稳定,出生后仅发生微小变化。第三类酶在胎儿体内不表达或表达水平较低,出生后1~2 年则明显升高。表观遗传调控是不涉及DNA序列改变的基因组修饰,主要包括DNA甲基化、组蛋白修饰及非编码RNAs调控。在肝脏发育过程中,表观遗传机制对DME发育表达发挥重要的调控作用。该综述全面回顾DME发育表达模式,揭示药物代谢与处置的潜在表观遗传调控机制,以明显提高儿童患者药物处置的预测能力,促进儿童患者合理、安全、有效用药。
Great changes in drug metabolizing enzyme(DME)expression occur in the fetus and child duringdevelopment.Individual hepatic DME ontogeny can be categorized into one of three groups based on developmental trajectories. Some enzymes such as CYP3A7, are expressed at highest level in the fetus during the first trimester and either remain elevated or slightly decrease during gestation, but are silenced or reduced to relatively low levels within one to two years after birth. SULT1A1 is an example of the second group of DME. These enzymes are expressed at relatively constant levels throughout gestation and into adulthood. CYP3A4 belongs to the third DME group.These enzymes are expressed at negligible or low levels in the fetus. Significant increases in enzyme levels are exhibited within the first one to two years after birth. The epigenetic regulation refers to genomic modifications that do not involve changes in DNA sequence and include DNA methylation, histone modifications, and non-coding RNAs.The epigenetic regulation mechanisms are responsible for the developmental expression of DME genes during liver maturation. This review will provide a summary of DME developmental expression profiles and reveal epigenetic mechanisms underlying variable drug metabolism and drug response. Thus, knowledge regarding DME ontogeny has permitted improved capability to predict drug disposition in pediatric patients, which is crucial for improving drug dosing leading to optimal safety and efficacy in children.


[1] Cuzzolin L, Atzei A, Fanos V. Off-label and unlicensed prescribing for newborns and children in different settings: a review of the literature and a consideration about drug safety[J]. Expert Opin Drug Saf, 2006, 5(5): 703-18.
[2] Pearce R E, Gotschall R R, Kearns G L,et al.Cytochrome P450 involvement in the biotransformation of cisapride and racemic norcisapride in vitro:differential activity of individual CYP3A isoforms[J]. Drug Metab Dispos, 2001, 29(12):1548-54.
[3] Klick D E, Shadley J D, Hines R N. Differential regulation of human hepatic flavin containing monooxygenase3(FMO3)by CCAAT/enhancer-binding protein beta(C/EBPbeta)liver inhibitory and liver activating proteins[J]. Biochem Pharmacol, 2008, 76(2): 268-78.
[4] Koukouritaki S B, Simpson P, Yeung C K, et al. Human hepatic flavin-containing monooxygenases 1(FMO1)and 3(FMO3)developmental expression[J]. Pediatr Res, 2002, 51(2): 236-43.
[5] Lacroix D, Sonnier M, Moncion A, et al. Expression of CYP3A in the human liver-evidence that the shift between CYP3A7 and CYP3A4 occurs immediately after birth[J]. Eur J Biochem, 1997, 247(2): 625-34.
[6] Stevens J C, Hines R N, Gu C, et al. Developmental expression of the major human hepatic CYP3A enzymes[J]. J Pharmacol Exp Ther, 2003, 307(2): 573-82.
[7] Williams J A, Hyland R, Jones B C, et al. Drug-drug interactions for UDP-glucuronosyltransferase substrates: a pharmacokinetic explanation for typically observed low exposure(AUCi/AUC)ratios[J]. Drug Metab Dispos, 2004, 32(11): 1201-8.
[8] Koukouritaki S B, Manro J R, Marsh S A, et al. Developmental expression of human hepatic CYP2C9 and CYP2C19[J]. J Pharmacol Exp Ther, 2004, 308(3): 965-74.
[9] Finta C, Zaphiropoulos P G. The human cytochrome P450 3A locus. Gene evolution by capture of downstream exons[J]. Gene, 2000, 260(1-2): 13-23.
[10] Strougo A, Yassen A, Monnereau C, et al. Predicting the “First dose in children” of CYP3A-metabolized drugs: evaluation of scaling approaches and insights into the CYP3A7-CYP3A4 switch at young ages[J]. J Clin Pharmacol, 2014, 54(9):1006-15.
[11] Vyhlidal C A, Pearce R E, Gaedigk R, et al. Variability in expression of CYP3A5 in human fetal liver[J]. Drug Metab Dispos, 2015,43(8):1286-93.
[12] He H, Nie Y L, Li J F, et al. Developmental regulation of CYP3A4 and CYP3A7 in Chinese Han population[J]. Drug Metab Pharmacokinet, 2016,31(6):433-44.
[13] Krueger S K, Williams D E. Mammalian flavin-containing monoooxygenases: structure/ function, genetic polymorphisms and role in drug metabolism[J]. Pharmacol Ther, 2005, 106(3): 357-87.
[14] Yeung C K, Lang D H, Thummel K E, et al. Immunoquantitation of FMO1 in human liver, kidney, and intestine[J]. Drug Metab Dispos, 2000, 28(9): 1107-11.
[15] Blanchard R L, Freimuth R R, Buck J, et al. A proposed nomenclature system for the cytosolic sulfotransferase(SULT)superfamily[J].Pharmacogenetics, 2004, 14(3): 199-211.
[16] Duanmu Z, Weckle A, Koukouritaki S B, et al. Developmental expression of aryl, estrogen, and hydroxysteroid sulfotransferases in pre- and postnatal human liver[J]. J Pharmacol Exp Ther, 2006, 316(3):1310-7.
[17] Hebbring S J, Adjei A A, Baer J L, et al. Human SULT1A1 gene: copy number differences and functional implications[J]. Hum Mol Genet, 2007, 16(5): 463-70.
[18] Vyhlidal C A, Gaedigk R, Leeder J S. Nuclear receptor expression in fetal and pediatric liver: correlation with CYP3A expression[J]. Drug Metab Dispos, 2006, 34(1): 131-7.
[19] 周 涛,王宇光,马增春,等. 银杏内酯 B 通过激活孕烷 X 受体诱导CYP3A4的表达[J].中国药理学通报, 2014, 30(7): 926-31.
[19] Zhou T, Wang Y G, Ma Z C, et al.Ginkgolide B induces CYP3A4 expression through activation of human pregnane X receptor[J]. Chin Pharmacol Bull, 2014,30(7): 926-31.
[20] Dallaire A, Simard M J. The implication of microRNAs and endo-siRNAs in animal germline and early development[J]. Dev Biol,2016, 416(1):18-25.
[21] Deaton A M, Bird A. CpG islands and the regulation of transcription[J]. Genes Dev, 2011, 25(10):1010-22.
[22] Meissner A, Mikkelsen T S, Gu H, et al. Genome-scale DNA methylation maps of pluripotent and differentiated cells[J]. Nature,2008, 454(7205): 766-70.
[23] Kacevska M, Ivanov M, Wyss A, et al. DNA methylation dynamics in the hepatic CYP3A4 gene promoter[J]. Biochimie, 2012, 94(11): 2338-44.
[24] Vyhlidal C A, Bi C, Ye S Q, et al. Dynamics of cytosine methylation in the proximal promoters of CYP3A4 and CYP3A7 in pediatric andprenatal liver[J]. Drug Metab Dispos, 2016, 44(7):1020-6.
[25] 张 玲,盛树力,秦 川. 表观遗传学药物的研究进展[J]. 中国药理学通报,2013, 29(3): 297-303.
[25] Zhang L, Sheng S L, Qin C.Research progress in epigenetic drug[J]. Chin Pharmacol Bull, 2013, 29(3): 297-303.
[26] Ingelman-Sundberg M, Zhong X B, Hankinson O, et al. Potential role of epigenetic mechanisms in the regulation of drug metabolism and transport[J]. Drug Metab Dispos, 2013, 41(10): 1725-31.
[27] Peng L, Zhong X. Epigenetic regulation of drug metabolism and transport [J]. Acta Pharm Sin B, 2015,5(2): 106-12.
[28] Lu H, Cui J Y, Gunewardena S, et al. Hepatic ontogeny and tissue distribution of mRNAs of epigenetic modifiers in mice using RNA-sequencing[J]. Epigenetics, 2012,7(8): 914-29.
[29] Ingelman-Sundberg M, Zhong X B, Hankinson O, et al. Potential role of epigenetic mechanisms in the regulation of drug metabolism and transport[J]. Drug Metab Dispos, 2013,41(10):1725-31.
[30] Li Y, Cui Y, Hart S N, et al. Dynamic patterns of histone methylation are associated with ontogenic expression of the Cyp3a genes during mouse liver maturation[J]. Mol Pharmacol, 2009, 75(5):1171-9.
[31] 王 沛,李晓天,张莉蓉. miRNAs 对药物代谢酶的转录后调控[J].中国药理学通报,2015, 31(8): 1037-40.
[31] Wang P, Li X T, Zhang L R. Post- transcription regulation of drug metabolic enzymes by miRNAs[J]. Chin Pharmacol Bull, 2015,31(8): 1037-40.
[32] Takagi S, Nakajima M, Kida K, et al. MicroRNAs regulate human hepatocyte nuclear factor 4alpha, modulating the expression of metabolic enzymes and cell cycle[J]. J Biol Chem, 2010, 285(7):4415 -22.


 WANG Yu guang,CHEN Qiang,LI Han,et al.The inhibitory effect of Rg1 on TCDD induced CYP1A1 in HepG2 cells[J].Chinese Pharmacological Bulletin,2013,(02):1382.
[2]李 辉,芮建中.microRNA对药物体内过程调控的研究进展[J].中国药理学通报,2017,(10):1345.[doi:10.3969/j.issn.1001-1978.2017.10.004]
 LI Hui,RUI Jian-zhong.The research progress of microRNA on regulation of drug disposition in vivo[J].Chinese Pharmacological Bulletin,2017,(02):1345.[doi:10.3969/j.issn.1001-1978.2017.10.004]


基金项目:国家自然科学基金资助项目(No 81173127,81273581)
作者简介:何 航(1971-),女,博士生,副教授,研究方向:遗传药理学、表观遗传药理学,E-mail:hehang03961971@163.com;
张莉蓉(1964-),女,博士,教授,博士生导师,研究方向:遗传药理学、表观遗传药理学,通讯作者, E-mail:zhanglirongzzu@126.com
更新日期/Last Update: 2017-02-15