遗传因素对白血病CYP3A5耐药机制的影响

目的:研究急性白血病(acute leukemia,AL)患者中,细胞色素P450 3A亚家族多肽5(cytochrome P450,subfamily ⅢA,polypeptide 5,CYP3A5)多态性、酶活性对患者发病、疗效和预后的影响.方法:采用PCR-限制性片段长度多态性(PCR-restriction fragment length polymorphism,PCR-RFLP)分析法,检测AL患者骨髓原代细胞CYP3A5*3突变频率,并应用高效液相色谱法(high performance liquid chromatography,HPLC)检测AL患者骨髓原代细胞CYP3A5酶的活性.结果:88例样本中野生型纯合子(CYP3A5*1/*1)23例(26%),杂合子(CYP3A5*1/*3)44例(50%),突变型纯合子(CYP3A5*3/*3)21例(24%).CYP3A5*3等位基因频率为74%,符合中国健康人群分布.按基因型分组后,3组的临床资料差异无统计学意义;3组的CYP3A5酶活性[以6β-羟基氢化可的松(6β-hydroxycortisol,6β-OHC)/氢化可的松(hydrocortisone,HC)值表示]检测结果分别为1.344±0.027、0.120±0.067和0.014±0.001;总生存率分别为(11.6±2.1)个月、(30.5±12.2)个月和(52.3±8.5)个月;无病生存期分别为(7.5±1.8)个月、(27.0±15.8)个月和(52.3±8.1)个月;差异均有统计学意义.结论:CYP3A5*3突变与AL发病无关,但可使CYP3A5酶活性显著降低或消失.含CYP3A5*1等位基因与耐药显著相关,从而影响患者的化疗疗效和预后.对初治AL患者进行CYP3A5基因分型和酶活性检测可以作为预测AL患者个体化治疗和预后的重要指标.     

CYP3A5*3基因多态性与晚期非小细胞肺癌患者应用多西他赛的疗效及安全性分析

目的:研究CYP3A5*3基因多态性对应用多西他赛治疗的晚期非小细胞肺癌患者的疗效以及安全性的相关性分析。方法:通过多基因检测技术明确患者CYP3A5*3的基因多态性状态，通过查阅随访表、病理以及随访电话明确患者的基本信息，包括性别、年龄、是否吸烟、EGFR状态和ECOG评分等，明确生存信息，即无进展生存期（PFS）和总生存期（OS）。通过不良反应表统计不良反应发生情况。用卡方检验对基因多态性与患者的不良反应进行相关性分析，用Kaplan-Meier生存曲线分析基因多态性与患者的PFS和OS的关系。结果:在生存分析方面，CYP3A5*3纯合突变型患者的中位总生存期约26个月，高于杂合型的24个月和野生型的22个月（P=0.833）。CYP3A5*3纯合突变型患者的中位无进展生存期4个月，也高于杂合型的2个月和野生型的3个月（P=0.306）。在不良反应方面，共有11例患者发生Ⅲ级以上骨髓抑制，其中7例（63.6%）患者为CYP3A5*3纯合突变型，考虑该基因型发生中重度骨髓抑制的可能性更大（P=0.415）。此外，有6例患者发生皮疹，其中5例（83.3%）为CYP3A5*3纯合突变型，还包括1例Ⅲ度皮疹。考虑该基因型患者发生皮疹的可能性更大（P=0.490）。手足综合征、神经毒性、肾毒性以及口腔黏膜炎等仅发生在 CYP3A5*3野生型及CYP3A5*3纯合突变型患者中。结论:应用多西他赛的晚期非小细胞肺癌患者中，CYP3A5*3纯合突变型患者的生存期高于杂合型和野生型患者。CYP3A5*3纯合突变型患者发生中重度骨髓抑制、皮疹的风险可能性更大。     

AKR7A3在肺腺癌中异常表达及临床意义

目的:探讨醛-酮还原酶家族7成员A3（AKR7A3）在肺腺癌中的异常表达及与临床病理特征的关系，并探究其临床意义。方法:采用生物信息学数据库分析、免疫组化、Western Blot、Real-time PCR等方法对肺腺癌组织及不同细胞中AKR7A3的表达进行检测与分析。结果:Oncomine数据库分析结果显示，在肺腺癌中，AKR7A3的表达普遍高于正常肺组织，分别为正常肺组织的1.811倍（P=0.022）、1.356倍（P<0.01）、1.413倍（P=0.002）。Kaplan-Meier Plotter数据库分析结果显示，AKR7A3高表达的患者较低表达的患者生存时间缩短，差异具有统计学意义（P=0.003 7）。免疫组化染色显示肺腺癌组织中AKR7A3的表达较癌旁增高，在与临床病理特征的相关性分析中，发现其与肿瘤分化程度（P<0.01）、淋巴结转移情况（P=0.029）以及TNM分期（P<0.01）相关，且会造成患者生存时间缩短（P=0.031）。Cox多因素分析表明AKR7A3可能是影响肺腺癌患者预后的独立危险因素(P=0.012)。Western Blot及Real-time PCR实验提示不同肺腺癌细胞中AKR7A3蛋白及mRNA表达普遍增高。结论:AKR7A3在肺腺癌中表达增高，对预后有不良影响，有促进肿瘤发生发展的作用。     

黄曲霉毒素B1诱发大鼠肝癌过程中对CYP3A4活性的影响

目的 探讨黄曲霉毒素B1(AFB1)诱发肝癌过程中对CYP3A4活性的影响.方法 采用大鼠肝微粒体混合酶体外代谢体系,利用荧光定量法动态检测AFB1诱发肝癌过程中不同时期CYP3A4酶活性.结果 AFB1组CYP3A4含量从实验开始逐渐升高,至23周达顶峰,然后逐渐降低,到43周又升高,出现双波峰变化,阶段性比较差异有统计学意义(P=0.000);对照组CYP3A4含量在整个实验过程中,除33周和63周出现明显降低外,其他各阶段变化不大;组间比较显示AFB1组在诱癌过程中有抑制CYP3A4的趋势,于63周抑制最明显,但尚未达统计学意义(P=0.638);结论AFB1在诱癌过程中有抑制CYP3A4的趋势,可能是与早期癌变的细胞减少对特定基因毒性物质的活化有关.     

人肺腺癌S100A6 mRNA表达与临床特征关系分析

目的:探讨肺腺癌组织S100A6 mRNA表达与患者临床特征的关系及其意义.方法:用RT-PCR方法检测98例手术后新鲜肺腺癌及癌旁正常肺组织S100A6 mRNA的表达,分析S100A6 mRNA表达与患者临床病理特征及生存预后的关系,ROC曲线法评价S100A6 mRNA表达对肺腺癌的诊断能力.结果:S100A6mRNA在肺腺癌组织中的表达显著高于正常肺组织(P＜0.01);S100A6 mRNA表达与患者性别和年龄无相关性(P＞0.05),而与吸烟指数、肿瘤分化、淋巴结转移、远处转移、TNM分期显著相关(P＜0.05).其中,肿瘤分化、TNM分期和S100A6mRNA表达是影响肺腺癌患者预后的独立因素.应用ROC曲线法评价S100A6mRNA表达对肺腺癌的诊断能力,其灵敏度、特异度、阳性预测值等指标均明显优于临床上传统肿瘤标志物.结论:S100A6 mRNA在肺腺癌组织中呈过表达,有望成为肺腺癌诊断、治疗评估及预后判断的重要指标.     

14-3-3ζ和E-cadherin在Ⅲ期肺腺癌中的表达及其意义

目的 检测Ⅲ期肺腺癌组织中14 3 3ζ和E 钙黏蛋白（E cadherin）的表达,并探讨其临床意义。方法 采用免疫组化SP法检测59例Ⅲ期肺腺癌组织和43例正常肺组织中14-3-3ζ与E-cadherin蛋白的表达水平,分析两者表达的相关性以及与临床病理特征和预后的关系。结果 14-3-3ζ在Ⅲ期肺腺癌组织中的高表达率为57.63％（34/59）,高于正常肺组织的30.23%（13/43）,差异有统计学意义（P＜0.05）;E-cadherin在肺腺癌组织中的高表达率为67.79%（40/59）,低于正常肺组织的72.09%（31/43）,差异无统计学意义（P＞0.05）。2种蛋白的表达均与肺腺癌的分化程度相关（P＜0.05）。Ⅲ期肺腺癌中14-3-3ζ与E-cadherin的表达呈显著正相关（r=0.351,P=0.015）。全组患者的中位生存时间（OS）为29.90个月。14-3-3ζ、E-cadherin高表达患者的中位OS均为52.63个月,优于低表达者的16.93个月（P＜0.05）。Cox多因素分析显示,14-3-3ζ是Ⅲ期肺腺癌预后的独立影响因素（HR=0.345,95%CI：0.153～0.777,P=0.010）。结论 14-3-3ζ与E-cadherin在Ⅲ期肺腺组织中的表达呈现较好的相关性,检测二者的表达对判断Ⅲ期肺腺癌患者的预后有一定提示作用。     

CYP3A5基因多态性与肿瘤的个体化治疗

CYP3A5是重要的药物代谢酶，主要的多态性是CYP3A5＊3突变，后者使CYP3A5表达和活性降低或消失，文章就CYP3A5＊3变异基因对肿瘤发生、治疗、预后的关系作一综述。     

肺腺癌组织SIRT1表达及其临床意义

目的 沉默信息调节因子1 (silent mating-type information regulation 2 homolog 1,SIRT1)与多种肿瘤的发生发展密切相关,但与肺腺癌的关系尚未明确.因此本研究将重点探讨肺腺癌组织中SIRT1的表达水平与临床病理参数和预后的关系,阐明其在肺腺癌发生发展中的作用.方法 肺腺癌芯片购自上海芯超生物科技有限公司,包括75例癌组织和配对癌旁正常组织(距切缘≥2 cm).采用免疫组织化学染色法,检测肺腺癌组织芯片中75例癌组织及配对癌旁正常组织中SIRT1的表达.x2检验分析SIRT1表达与临床病理特征的关系;Kaplan-Meier法及Log-rank检验分析临床病理参数和SIRT1表达与总生存期(overall survival,OS)的关系;拟合多因素Cox模型,采用风险比(hazard ratio,HR)评价不同临床指标与死亡风险的相关性.结果 肺腺癌组织中SIRT1的表达高于癌旁正常组织,H-score评分均值分别为260和113,P＜0.001;肺腺癌组织中SIRT1的表达水平与患者的性别(P=0.232)、年龄(P=0.318)、淋巴结转移(P=0.377)、肺腺癌亚型(P=0.245)、远处转移(P=1.000)和TNM分期(P=0.216)无显著相关性,而与病理分级显著相关,P=0.029.SIRT1高表达组肺腺癌患者的死亡风险较低表达组显著增加,单因素显示,HR=3.991,95％CI为1.411～11.288,P=0.009;多因素回归分析显示,HR=4.388,95％CI为1.192～16.155,P=0.026.结论 肺腺癌组织SIRT1表达与病理分级显著相关,且SIRT1高表达提示肺腺癌预后较差.     

CYP3A4在黄曲霉毒素B1诱发大鼠肝癌过程中的表达及意义

探讨CYP3A4在黄曲霉毒素B1（AFB1）实验诱发大鼠肝癌过程中的活性变化及其在肝癌发生过程中的意义。方法:雄性、4周龄、Wistar大鼠随机分为AFB1组和对照组;AFB1组腹腔注射AFB1,对照组则给与溶媒二甲基亚砜。在诱发肝癌过程中,分别于第13、23、33、43、53、63周对大鼠进行肝活检;实验至第73周处死全部动物取肝组织;利用大鼠肝组织微粒体混合酶体外代谢体系,采用荧光分光光度定量法动态检测肝标本中CYP3A4酶活性。结果:AFB1组肝细胞癌发生率为58.8%（10/17）;对照组肝细胞癌发生率为0（0/16）,两组间肝癌发生率比较,AFB1组显著高于对照组（P=0.001）。两组大鼠肝组织代谢酶CYP3A4活性都有不同程度的变化。肝组织CYP3A4活性从13 w开始逐渐升高,至23 w达顶峰,然后逐渐降低,到43 w又升高,出现双波峰变化;从13 w至53 w不同时段AFB1组肝组织CYP3A4活性显著低于对照组（P<0.01）。但是至63 w时AFB1组肝组织CYP3A4活性基本接近对照组（P=0.5086）。结论:CYP3A4活性在AFB1诱癌过程中受到抑制,可能是由于癌变早期的细胞减少对致癌物质的活化有关;CYP3A4活性在AFB1诱癌过程中的表达起伏变化,是由于基因多态性较大程度上影响蛋白表达水平的结果。      

广西崇左HBsAg阳性人群CYP3A5的基因多态性

目的:探讨HBsAg阳性人群中CYP3A5基因多态性与肝癌遗传易感性的关系。方法:通过癌症筛查发现广西崇左市HBsAg阳性人群,选取肝癌家族HBsAg阳性成员109例（研究组）及与之相对应的无肿瘤家族HBsAg阳性成员109例（对照组）作为研究对象,用PCR-RFLP法检测CYP3A5基因。结果:研究组AA基因型的分布与对照组有显著性差异（P＜0.05）。研究组A等位基因的分布与对照组有显著性差异（P＜0.05）。结论:CYP3A5基因多态性与肝癌的遗传易感性密切相关。     

CYP3A4, CYP3A5, and CYP3A43 genotypes and haplotypes in the etiology and severity of prostate cancer

The CYP3A genes reside on chromosome 7q21 in a multigene cluster. The enzyme products of CYP3A4 and CYP3A43 are involved in testosterone metabolism. CYP3A4 and CYP3A5 have been associated previously with prostate cancer occurrence and severity. To comprehensively examine the effects of these genes on prostate cancer occurrence and severity, we studied 622 incident prostate cancer cases and 396 controls. Substantial and race-specific linkage disequilibrium was observed between CYP3A4 and CYP3A5 in both races but not between other pairs of loci. We found no association of CYP3A5 genotypes with prostate cancer or disease severity. CYP3A43*3 was associated with family history-positive prostate cancer (age- and race-adjusted odds ratio = 5.86, 95% confidence interval, 1.10-31.16). CYP3A4*1B was associated inversely with the probability of having prostate cancer in Caucasians (age-adjusted odds ratio = 0.54, 95% confidence interval, 0.32-0.94). We also observed significant interactions among these loci associated with prostate cancer occurrence and severity. There were statistically significant differences in haplotype frequencies involving these three genes in high-stage cases (P < 0.05) compared with controls. The observation that CYP3A4 and CYP3A43 were associated with prostate cancer, are not in linkage equilibrium, and are both involved in testosterone metabolism, suggest that both CYP3A4*1B and CYP3A43*3 may influence the probability of having prostate cancer and disease severity.     

CYP3A4 and CYP3A5 genotypes, haplotypes, and risk of prostate cancer.

Previous case-only studies have shown that men with the CYP3A4*1B promoter variant are at an increased risk of developing more aggressive forms of prostate cancer. However, no changes in CYP3A4 activity have been found in CYP3A4*1B carriers, suggesting that its association with disease may simply reflect linkage disequilibrium with another functional variant. CYP3A5 is located within 200 kb of CYP3A4, and a variant in CYP3A5 (*1/*3) correlates with function of the CYP3A5 enzyme. In this study, the potential effect of CYP3A4*1B and CYP3A5*1 on prostate cancer risk and aggressiveness were evaluated in a family-based case-control population. The CYP3A4*1B variant was positively associated with prostate cancer among Caucasians with more aggressive disease [odds ratio (OR), 1.91; 95% confidence interval (CI), 1.02-3.57; P=0.04], and inversely associated with risk among Caucasians with less aggressive disease (OR, 0.08; 95% CI, 0.01-0.49; P=0.006) and men with an age of diagnosis <63 (OR, 0.51; 95% CI, 0.26-1.00; P=0.05). The CYP3A5*1 variant was inversely associated with prostate cancer, especially among Caucasians with less aggressive disease (OR, 0.42; 95% CI, 0.22-0.78; P=0.006). As expected based on these genotype-level results, the CYP3A4*1B/CYP3A5*3 haplotype was positively associated with disease (OR, 2.91; 95% CI, 1.36-6.23; P=0.006), and the CYP3A4*1B/CYP3A5*1 haplotype was inversely associated with risk among Caucasians with less aggressive disease (OR, 0.07; 95% CI, 0.01-0.51; P=0.009). These findings suggest that the CYP3A4 and CYP3A5 variants, or other alleles on the haplotypes they help distinguish, are associated with prostate cancer risk and aggressiveness.     

Association of CYP3A4, CYP3A5 polymorphisms with lung cancer risk in Bangladeshi population

The rate of direct smoking, second hand smoking, and smokeless tobacco users as well as the amount of environmental pollutant like polycyclic aromatic hydrocarons is increasing in Bangladesh. Therefore, the prevalence of lung cancer is increasing day by day. To the best of our knowledge, no pharmacogentic study of CYP3A4, CYP3A5 genes has been reported on Bangladeshi population relating those with lung cancer. The present study was conducted to determine the association of CYP3A4, CYP3A5 gene polymorphisms and tobacco smoking in the development of lung cancer in Bangladeshi population. A case–control study was carried out on 106 lung cancer patients and 116 controls to investigate three allelic variants—CYP3A4*1B, CYP3A5*3, and CYP3A5*6 using Polymerase Chain Reaction Restriction Fragment Length Polymorphism. Risk of lung cancer was estimated as odds ratio (OR) and 95 % confidence interval (CI) using unconditional logistic regression models. The variant allele frequencies for CYP3A4*1B (*1A/*1B?+?*1B/*1B) were 2.83 % and 0.86 % and that of CYP3A5*3 (*1A/*3?+?*3/*3) were 88.68 % and 85.34 % in cases and controls, respectively. Individual carrying at least one variant allele of CYP3A4*1B (CYP3A4*1A/1B?+?*1B/1B) has a 3.35 times more risk (OR?=?3.35, 95 % Cl?=?0.34-32.71, p?=?0.271) for developing lung cancer whereas individual carrying at least one variant allele of CYP3A5 (CYP3A5*1A/3?+?*3/3) has a 1.26 times more risk (OR?=?1.35, 95 % Cl?=?0.61–2.97) and both are statistically non-significant (p?>?0.05). CYP3A5*6 was absent in the study population. No association of lung cancer with the mentioned polymorphisms was found both in heavy and light smokers. In the cases of all three major types of lung cancer—squamous cell carcinoma, adenocarcinoma, and small cell carcinoma—significantly strong relationships (p???0.05) have been found. To confirm the association of lung cancer with the mentioned polymorphisms, large number volunteers (patients and controls) will be required.     

Analysis of CYP3A5*3 and CYP3A5*6 Gene Polymorphismsin Indian Chronic Myeloid Leukemia Patients

CYP3A5 is a member of the CYP3A gene family which metabolizes 50% of therapeutic drugs and steroidhormones. CYP3A5*3 and CYP3A5*6 polymorphisms exhibit inter-individual differences in CYP3A5 expression.The CYP3A5*3 allele (A6986G transition in intron 3) results in loss of CYP3A5 expression and the CYP3A5*6allele (G14690A transition in exon 2, leading to the skipping of exon 7) is associated with lower CYP3A5 catalyticactivity. The aim of the present study was to investigate their influence on susceptibility to chronic myeloidleukemia (CML). 265 CML cases and 241 age and sex matched healthy controls were analyzed by the PCR-RFLPtechnique. The frequencies of homozygous 3/3 genotype and CYP3A5*3 allele were elevated significantly in theCML group compared to controls (χ2=93.15, df=2, p=0.0001). With respect to clinical parameters, CYP3A5*3allele frequency was increased in patients with advanced phase of the disease (0.71) as compared to those inchronic phase (0.65). Patients without hematological response (minor/poor) had higher frequency of 3/3 genotype(54.54%) as compared to those with major hematological response (41.2%). CYP3A5*6 allele was not observed incases as well as in controls. Our study suggests that the CYP3A5*3 gene polymorphism is significantly associatedwith the risk of CML development and disease progression.     

Metabolism of irinotecan (CPT-11) by CYP3A4 and CYP3A5 in humans.

7-Ethyl-10[4-(1-piperidino)-1-piperidino] carbonyloxy-camptothecin (CPT-11), a DNA topoisomerase I inhibitor, undergoes several metabolic pathways to generate conjugated and unconjugated derivatives that could be excreted from the body. The objective of this study was to determine the oxidative metabolites of CPT-11 recovered in human urine samples and to identify cytochrome P450 (CYP) involved in their formation. In addition to the already known metabolites of CPT-11 [SN-38, SN-38-G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin (APC), and 7-ethyl-10-(4-amino-1-piperidino) carbonyloxycamptothecin (NPC)], we isolated three oxidized metabolites from the urine of two children and two adults given CPT-11. M1 and M2 (molecular weight, 602) were hydroxylated, respectively, on the CPT moiety and on the terminal piperidine ring of CPT-11. M3 had a molecular mass of 602, but its urine concentration in patients was too low to establish its chemical structure by liquid chromatography/mass spectrometry. In vitro incubations with cells expressing CYP2C8, CYP2C9, CYP1A1, CYP1A2, or CYP3A7 did not produce any detectable metabolites. Only CYP3A4 produced both APC and NPC, resulting from the oxidation of the piperidinylpiperidine side chain of CPT-11 along with metabolite M2. The metabolism of CPT-11 by CYP3A5 was markedly different because neither APC or NPC nor M2 was produced, whereas only one new metabolite, M4 (molecular weight, 558), was generated by de-ethylation of the CPT moiety. No previous study has reported the presence of the M4 metabolite. Production of APC, NPC, M2, and M4 was prevented by ketoconazole, a specific CYP3A inhibitor. The parameters of CPT-11 biotransformation into M2 and M4 were examined using cell lines expressing, respectively, with CYP3A4 and CYP3A5, indicating that CPT-11 is preferentially metabolized by CYP3A4. In conclusion, CYP3A plays a major role in the metabolism of CPT-11, with some differences of the metabolic profile exhibited by 3A4 and 3A5.     

Association of CYP2C8, CYP3A4, CYP3A5, and ABCB1 polymorphisms with the pharmacokinetics of paclitaxel.

PURPOSE: To retrospectively evaluate the effects of six known allelic variants in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes on the pharmacokinetics of the anticancer agent paclitaxel (Taxol). EXPERIMENTAL DESIGN: A cohort of 97 Caucasian patients with cancer (median age, 57 years) received paclitaxel as an i.v. infusion (dose range, 80-225 mg/m(2)). Genomic DNA was analyzed using PCR RFLP or using Pyrosequencing. Pharmacokinetic variables for unbound paclitaxel were estimated using nonlinear mixed effect modeling. The effects of genotypes on typical value of clearance were evaluated with the likelihood ratio test within NONMEM. In addition, relations between genotype and individual pharmacokinetic variable estimates were evaluated with one-way ANOVA. RESULTS: The allele frequencies for the CYP2C8*2, CYP2C8*3, CYP2C8*4, CYP3A4*3, CYP3A5*3C, and ABCB1 3435C>T variants were 0.7%, 9.2%, 2.1%, 0.5%, 93.2%, and 47.1%, respectively, and all were in Hardy-Weinberg equilibrium. The population typical value of clearance of unbound paclitaxel was 301 L/h (individual clearance range, 83.7-1055 L/h). The CYP2C8 or CYP3A4/5 genotypes were not statistically significantly associated with unbound clearance of paclitaxel. Likewise, no statistically significant association was observed between the ABCB1 3435C>T variant and any of the studied pharmacokinetic variables. CONCLUSIONS: This study indicates that the presently evaluated variant alleles in the CYP2C8, CYP3A4, CYP3A5, and ABCB1 genes do not explain the substantial interindividual variability in paclitaxel pharmacokinetics.     

Association between the CYP3A4 and CYP3A5 polymorphisms and cancer risk: a meta-analysis and meta-regression

Previously published data on the association between CYP3A4 A392G and CYP3A5 Met235Thr polymorphisms and the risk of cancer remained controversial. Thus, we performed a meta-analysis to investigate the association between cancer susceptibility and CYP3A4 A392G (18,629 cases and 22,323 controls from 49 studies) and CYP3A5 Met235Thr polymorphisms (14,334 cases and 18,183 from 39 studies) in different inheritance models. We used odds ratios with 95 % confidence intervals to assess the strength of the association. Overall, significant association was found between CYP3A4 A392G polymorphism and cancer susceptibility (dominant model, odds ratio (OR) = 1.19; 95 % confidence interval (CI) = 1.03–1.38). In the further stratified and sensitivity analyses, significant increased prostate cancer risk was found among Caucasians (dominant model, OR?=?1.88; 95 % CI?=?1.20–2.95; recessive model, OR?=?2.10; 95 % CI?=?1.23–3.60; additive model, OR?=?1.80, 95 % CI?=?1.24–2.63; homozygous model, OR?=?2.34, 95 % CI?=?1.36–4.03; heterozygote model, OR?=?1.79, 95 % CI?=?1.11–2.89) for CYP3A4 A392G. For CYP3A5 Met235Thr polymorphism, no significant association was found among overall analysis and any subgroup analysis. In summary, this meta-analysis suggests that CYP3A4 A392G polymorphism is associated with increased prostate cancer risk among Caucasians and CYP3A5 Met235Thr polymorphism is not associated with the risk of cancer.     

Genotype relationships in the CYP3A locus in Caucasians

Genetic polymorphisms of the human CYP3A family affect clinical drug efficacy and may modify cancer risk. CYP3A genes show high sequence similarity that had previously lead to misallocation of CYP3A polymorphisms. Recent studies indicated a high degree of or even complete linkage for certain CYP3A alleles. Reliable LightCycler-based genotyping methods were developed and their degree of linkage in a large Caucasian population (n = 1210) investigated. Strong linkage disequilibrium was confirmed between CYP3A4, CYP3A5, and CYP3AP1 (each at P < 10(-5)). Contrary to some previous results claiming complete linkage between the phenotypically relevant CYP3A5*1 and a variant in a pseudogene promoter region CYP3AP1*1 we found among 428 controls (15 of 66) and 782 lung cancer cases (25 of 115) approximately 22% of CYP3AP1*1 carriers to be homozygous for CYP3A5*3 We conclude that contrary to previous assumptions, the CYP3AP1 genotype is not a reliable predictor for CYP3A5 activity.     

Polymorphism analysis of CYP3A5 in myeloid leukemia

The human cytochrome P450 (CYP) metabolizes more than 100 structurally diverse exogenous and endogenous molecules. The CYP3A5 is a major P450 enzyme in the liver and represents 50% of the total hepatic CYP3A content in people expressing CYP3A5. The single nucleotide polymorphisms in CYP3A5*3 and CYP3A5*6 that resulted in the absence of CYP3A5 from tissues were noted in some people. Polymorphisms of potential relevance to leukemia and myelodysplastic syndrome (MDS) have been described for various CYP. The bone marrow and/or peripheral blood from 188 acute myeloid leukemia (AML) patients, 101 chronic myeloid leukemia (CML), 40 MDS, and 270 normal controls were analyzed by a PCR-RFLP assay to evaluate the association of the CYP3A5 polymorphisms with myeloid leukemia. Our data showed that 15/188 (8%), 8/101 (7.9%), and 3/40 (7.5%) of the patients (i.e., 188 AML, 101 CML, 40 MDS) were CYP3A5*1/*1; 88/188 (46.8%), 47/101 (46.5%), and 20/40 (50%) were CYP3A5*1/*3; and 85/188 (45.2%), 46/101 (45.5%), and 17/40 (42.5%) carried the CYP3A5*3/*3 genotype, respectively. CYP3A5*6 was not found in any of the patients' specimens. Similar frequencies of CYP3A5*3 were observed in the leukemic patients and normal controls. Consequently, the finding suggests that the CYP3A5 polymorphism was not associated with the risk of myeloid leukemia.     

Effect of common CYP3A4 and CYP3A5 variants on the pharmacokinetics of the cytochrome P450 3A phenotyping probe midazolam in cancer patients.

PURPOSE: To evaluate the effect of naturally occurring variants in genes encoding the cytochrome P450 (CYP) isoforms CYP3A4 and CYP3A5 in patients with cancer receiving midazolam as a phenotyping probe. EXPERIMENTAL DESIGN: Five variants in CYP3A4 and CYP3A5 were evaluated in 58 patients (21 women and 37 men) receiving a short i.v. bolus of midazolam (dose, 0.0145 or 0.025 mg/kg). Midazolam concentrations in plasma were determined using liquid chromatography-mass spectrometry, and pharmacokinetic variables were calculated using noncompartmental analysis. Genomic DNA was characterized for the variants by PCR-RFLP, and all genotypes were confirmed by direct nucleotide sequencing. RESULTS: The mean clearance of midazolam was 24.4 +/- 9.12 L/h, and phenotypic CYP3A activity varied about 4-fold in this population (range, 10.8-44.3 L/h). There were six carriers of the CYP3A4*1B allele (allele frequency, 0.061). No variant alleles for CYP3A4*17, CYP3A4*18A, or CYP3A5*6 were identified. Forty-eight of the 58 patients were homozygous variant for CYP3A5*3C, eight were heterozygous, and two were homozygous wild type (allele frequency, 0.897). No associations were noted between any of the studied genotypes and the phenotypic measures (P > or = 0.16). Likewise, a common variant in exon 26 in the gene encoding P-glycoprotein [i.e., ABCB1 (MDR1) 3435C>T] that was previously reported to be linked to CYP3A4 mRNA levels was unrelated to any of the studied phenotypic measures (P > or = 0.49). CONCLUSIONS: The studied genetic variants in CYP3A4 and CYP3A5 are unlikely to have an important functional significance to phenotypic CYP3A activity in patients with cancer.