OATP1B1和CYP3A5*3基因多态性与抗结核药物性肝损伤的相关性分析
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摘要
目的分析OATP1B1和CYP3A5*3基因多态性与抗结核药物性肝损伤的关系。方法采用病例对照研究设计,随机选取抗结核治疗致肝损伤的患者160例为病例组,无肝损伤的结核患者145例为对照组,采用聚合酶链反应限制性片段长度多态法(PCR-RFLP)检测OATP1B1-388A>G位点及CYP3A5*3-6986A>G位点多态性;利用SPSS21.0软件对基因型分布进行χ2检验,并进行多因素logistics回归分析。结果病例组和对照组比较性别、吸烟者比例差异无统计学意义(P>0.05);饮酒者比例两组间比较差异有统计学意义(OATP1B1-388A>G,χ2=6.900,P<0.01;CYP3A5*3-6986A>G,χ~2=8.322,P<0.01),即与肝损伤具有相关性;OATP1B1-388A>G位点及CYP3A5*3-6986A>G位点的各基因型在两组中的分布差异均有统计学意义(P<0.01),其突变频率分别为70.82%和70.16%。多因素logistics回归分析调整饮酒因素后,OATP1B1-388A>G位点及CYP3A5*3-6986A>G位点的突变型(AG、GG)仍为ADLI的危险因素,但二者在抗结核药致肝损伤的过程中无交互作用。结论OATP1B1-388A>G位点及CYP3A5*3-6986A>G位点的多态性与ADLI的发生具有相关性,其中突变型可使ADLI发生风险增加。
Objective To examine the relationship between polymorphisms of the organic anion transporting polypeptide(OATP1 B1)gene and the cytochrome P450 3 A5*3(CYP3 A5*3)gene and anti-tuberculosis drug-induced liver injury(ADLI). Methods A case-control study was conducted.One hundred and sixty patients with tuberculosis and ADLI served as cases,and 145 patients with tuberculosis without liver injury served as controls.Polymerase chain reactionrestriction fragment length polymorphism(PCR-RFLP)was used to identify the genotypes of the OATP1 B1-388 A>G gene and the CYP3 A5*3-6986 A>G gene.Data on genotype distribution was analyzed using the software SPSS 21.0,and multi-factor regression analysis was performed using logistic regression. Results Gender and smoking did not differ in cases and controls(P>0.05);Alcohol consumption differed significantly in the two groups(OATP1 B1-388 A>G,χ~2=6.900,P<0.01,CYP3 A5*3-6986 A>G,χ2=8.322,P<0.01),which indicated that alcohol consumption was associated with liver injury.The frequency of AA and AG/GG in OATP1 B1-388 A>G was respectively 21.88%and 78.12%in cases and 37.24% and 62.76%in controls,while the frequency of AA and AG/GG in CYP3 A5*3-6986 A>G was18.12%and 81.88%in cases and 42.76% and 57.24%in controls.Results indicated that the frequency of both mutations differed significantly in the two groups(P<0.01).The frequency of a mutation was respectively 70.82% and 70.16%in the two groups.After adjusting for alcohol consumption as a factor in multi-factor regression analysis,mutations(AG and GG)in OATP1B1(388 A>G)and CYP3 A5*3(6986 A>G)were still risk factors for ADLI.However,the two mutations did not interact in liver injury induced by antituberculosis drugs. Conclusion The OATP1 B1-388 A>G and CYP3 A5*3-6986 A>G polymorphisms were correlated with ADLI,and those mutations were deemed to be risk factors for ADLI.
Objective To examine the relationship between polymorphisms of the organic anion transporting polypeptide(OATP1 B1)gene and the cytochrome P450 3 A5*3(CYP3 A5*3)gene and anti-tuberculosis drug-induced liver injury(ADLI). Methods A case-control study was conducted.One hundred and sixty patients with tuberculosis and ADLI served as cases,and 145 patients with tuberculosis without liver injury served as controls.Polymerase chain reactionrestriction fragment length polymorphism(PCR-RFLP)was used to identify the genotypes of the OATP1 B1-388 A>G gene and the CYP3 A5*3-6986 A>G gene.Data on genotype distribution was analyzed using the software SPSS 21.0,and multi-factor regression analysis was performed using logistic regression. Results Gender and smoking did not differ in cases and controls(P>0.05);Alcohol consumption differed significantly in the two groups(OATP1 B1-388 A>G,χ~2=6.900,P<0.01,CYP3 A5*3-6986 A>G,χ2=8.322,P<0.01),which indicated that alcohol consumption was associated with liver injury.The frequency of AA and AG/GG in OATP1 B1-388 A>G was respectively 21.88%and 78.12%in cases and 37.24% and 62.76%in controls,while the frequency of AA and AG/GG in CYP3 A5*3-6986 A>G was18.12%and 81.88%in cases and 42.76% and 57.24%in controls.Results indicated that the frequency of both mutations differed significantly in the two groups(P<0.01).The frequency of a mutation was respectively 70.82% and 70.16%in the two groups.After adjusting for alcohol consumption as a factor in multi-factor regression analysis,mutations(AG and GG)in OATP1B1(388 A>G)and CYP3 A5*3(6986 A>G)were still risk factors for ADLI.However,the two mutations did not interact in liver injury induced by antituberculosis drugs. Conclusion The OATP1 B1-388 A>G and CYP3 A5*3-6986 A>G polymorphisms were correlated with ADLI,and those mutations were deemed to be risk factors for ADLI.
引文
[1] Schutz C,Ismail Z,Proxenos CJ,et al.Burden of antituberculo-sis and antiretroviral drug-induced liver injury at a secondary hos-pital in South Africa[J].S Afr Med J,2012,102(6):506-11.
[2] Huang YS.Genetic polymorphisms of drug-metabolizing enzymesand the susceptibility to antituberculosis drug-induced liver injury[J].Expert Opini Drug Metab Toxicol,2007,3(1):1-8.
[3] 高丽,李世明,史哲,等.GSTA1/GSTM3基因多态性与抗结核药物性肝损伤的相关性分析[J].中华疾病控制杂志,2014(7):585-9.
[4] 张晓庆,郝晓晖,张利斌,等.CYP2C19基因多态性与抗结核药物性肝损害的关系研究[J].中国药房,2014(10):887-90.
[5] 刘瑜,高瑞,陈昱,等.抗结核药所致肝损害与药物代谢酶等基因多态性的关联性研究[J].中国临床药理学与治疗学,2015,20(1):91-5.
[6] 杨凡,张梅.药物转运体有机阴离子转运多肽1B1基因多态性的研究进展[J].医药导报,2013(10):1329-33.
[7] Romaine SP,Bailey KM,Hall AS,et al.The influence of SL-CO1B1(OATP1B1)gene polymorphisms on response to statintherapy[J].Pharmacogenomics J,2010,10(1):1-11.
[8] 谭玮,李燕.有机阴离子转运肽在药物转运中的作用[J].国际药学研究杂志,2007(5):364-8.
[9] Hu YF,He J,Chen GL,et al.CYP3A5*3and CYP3A4*18single nucleotide polymorphisms in a Chinese population[J].ClinChim Acta 2005,353(1-2):187-92.
[10] Burk O,Koch I,Raucy J,et al.The induction of cytochromeP450 3A5(CYP3A5)in the human liver and intestine is mediatedby the xenobiotic sensors pregnane X receptor(PXR)and consti-tutively activated receptor(CAR)[J].J Biol Chem,2004,279(37):38379-85.
[11] Anzenbacherova E,Spicakova A,Jourova L,et al.Interactionof rocuronium with human liver cytochromes P450[J].J Phar-macol Sci,2015,127(2):190-5.
[12] Izumi S,Nozaki Y,Komori T,et al.Substrate-dependent inhi-bition of organic anion transporting polypeptide 1B1:comparativeanalysis with prototypical probe substrates estradiol-17beta-glucu-ronide,estrone-3-sulfate,and sulfobromophthalein[J].DrugMetab Dispos,2013,41(10):1859-66.
[13] Ieiri I,Higuchi S,Sugiyama Y.Genetic polymorphisms of up-take(OATP1B1,1B3)and efflux(MRP2,BCRP)transporters:implications for inter-individual differences in the pharmacokinet-ics and pharmacodynamics of statins and other clinically relevantdrugs[J].Expert Opin Drug Metab Toxicol,2009,5(7):703-29.
[14] Wen J,Xiong Y.OATP1B1 388A>G polymorphism and phar-macokinetics of pitavastatin in Chinese healthy volunteers[J].JClin Pharm Ther,2010,35(1):99-104.
[15] Niemi M,Pasanen MK,Neuvonen PJ.Organic anion transpor-ting polypeptide 1B1:agenetically polymorphic transporter ofmajor importance for hepatic drug uptake[J].Pharmacol Rev,2011,63(1):157-81.
[16] Li LM,Chen L,Deng GH,et al.SLCO1B1*15haplotype isassociated with rifampin-induced liver injury[J].Mol Med Rep,2012,6(1):75-82.
[17] 孙荣,毕雅坤,欧维正,等.贵州省结核分枝杆菌临床分离株MIRU-VNTR位点基因分型研究[J].中国病原生物学杂志,2017,12(1):29-33.
[18] 李灵敏,陈磊,陈文生.OATP1B1基因多态性与抗结核药物肝损害的关联研究[J].中华临床医师杂志(电子版),2013(24):11376-9.
[19] 郭桐君,李玉红,朱凌妍,等.CYP3A5*3和CYP3A4*18B基因多态性与抗结核药物性肝损伤的关系[J].中华疾病控制杂志,2016,20(9):897-900,9.
[20] Chang KC,Leung CC,Yew WW,et al.Hepatotoxicity ofpyrazinamide:cohort and case-control analyses[J].Am J RespCrit Care,2008,177(12):1391-6.
[2] Huang YS.Genetic polymorphisms of drug-metabolizing enzymesand the susceptibility to antituberculosis drug-induced liver injury[J].Expert Opini Drug Metab Toxicol,2007,3(1):1-8.
[3] 高丽,李世明,史哲,等.GSTA1/GSTM3基因多态性与抗结核药物性肝损伤的相关性分析[J].中华疾病控制杂志,2014(7):585-9.
[4] 张晓庆,郝晓晖,张利斌,等.CYP2C19基因多态性与抗结核药物性肝损害的关系研究[J].中国药房,2014(10):887-90.
[5] 刘瑜,高瑞,陈昱,等.抗结核药所致肝损害与药物代谢酶等基因多态性的关联性研究[J].中国临床药理学与治疗学,2015,20(1):91-5.
[6] 杨凡,张梅.药物转运体有机阴离子转运多肽1B1基因多态性的研究进展[J].医药导报,2013(10):1329-33.
[7] Romaine SP,Bailey KM,Hall AS,et al.The influence of SL-CO1B1(OATP1B1)gene polymorphisms on response to statintherapy[J].Pharmacogenomics J,2010,10(1):1-11.
[8] 谭玮,李燕.有机阴离子转运肽在药物转运中的作用[J].国际药学研究杂志,2007(5):364-8.
[9] Hu YF,He J,Chen GL,et al.CYP3A5*3and CYP3A4*18single nucleotide polymorphisms in a Chinese population[J].ClinChim Acta 2005,353(1-2):187-92.
[10] Burk O,Koch I,Raucy J,et al.The induction of cytochromeP450 3A5(CYP3A5)in the human liver and intestine is mediatedby the xenobiotic sensors pregnane X receptor(PXR)and consti-tutively activated receptor(CAR)[J].J Biol Chem,2004,279(37):38379-85.
[11] Anzenbacherova E,Spicakova A,Jourova L,et al.Interactionof rocuronium with human liver cytochromes P450[J].J Phar-macol Sci,2015,127(2):190-5.
[12] Izumi S,Nozaki Y,Komori T,et al.Substrate-dependent inhi-bition of organic anion transporting polypeptide 1B1:comparativeanalysis with prototypical probe substrates estradiol-17beta-glucu-ronide,estrone-3-sulfate,and sulfobromophthalein[J].DrugMetab Dispos,2013,41(10):1859-66.
[13] Ieiri I,Higuchi S,Sugiyama Y.Genetic polymorphisms of up-take(OATP1B1,1B3)and efflux(MRP2,BCRP)transporters:implications for inter-individual differences in the pharmacokinet-ics and pharmacodynamics of statins and other clinically relevantdrugs[J].Expert Opin Drug Metab Toxicol,2009,5(7):703-29.
[14] Wen J,Xiong Y.OATP1B1 388A>G polymorphism and phar-macokinetics of pitavastatin in Chinese healthy volunteers[J].JClin Pharm Ther,2010,35(1):99-104.
[15] Niemi M,Pasanen MK,Neuvonen PJ.Organic anion transpor-ting polypeptide 1B1:agenetically polymorphic transporter ofmajor importance for hepatic drug uptake[J].Pharmacol Rev,2011,63(1):157-81.
[16] Li LM,Chen L,Deng GH,et al.SLCO1B1*15haplotype isassociated with rifampin-induced liver injury[J].Mol Med Rep,2012,6(1):75-82.
[17] 孙荣,毕雅坤,欧维正,等.贵州省结核分枝杆菌临床分离株MIRU-VNTR位点基因分型研究[J].中国病原生物学杂志,2017,12(1):29-33.
[18] 李灵敏,陈磊,陈文生.OATP1B1基因多态性与抗结核药物肝损害的关联研究[J].中华临床医师杂志(电子版),2013(24):11376-9.
[19] 郭桐君,李玉红,朱凌妍,等.CYP3A5*3和CYP3A4*18B基因多态性与抗结核药物性肝损伤的关系[J].中华疾病控制杂志,2016,20(9):897-900,9.
[20] Chang KC,Leung CC,Yew WW,et al.Hepatotoxicity ofpyrazinamide:cohort and case-control analyses[J].Am J RespCrit Care,2008,177(12):1391-6.