中国人群N—乙酰转移酶多态性的基因分析

AIM: To study the genetic basis of N-acetylatransferase polymorphism in Chinese. METHODS: Genotypes in 120 healthy Han volunteers from 19 provinces of China were assayed. The 3 common mutant alleles (M1, M2, M3) and one normal wild-type (WT) allele of the N-acetyltransferase (NAT2) gene were detected by allele-specific polymerase chain reaction technique. RESULTS: The NAT2 allele frequencies in 120 Chinese (WT = 0.625, M1 = 0.0458, M2 = 0.188, M3 = 0.142) were different (P < 0.01). The NAT2 genotype distribution for all detected combinations of NAT2 alleles in 120 Chinese subjects was consisitent with Hardy-Weinberg equilibrium (chi 2 = 7.27, nu = 8, 0.7 > P > 0.5). Fifty subjects (41.7%) were homozygous wildtypes, 50 subjects (41.7%) were heterozygous mutants, and 20 subjects (16.7%) were homozygous mutants. CONCLUSION: The lower frequency of mutant M1 allele compared with that of Caucasians explains the low frequency of slow acylators in Chinese.     

N-乙酰转移酶影响食管癌细胞生物学功能的研究

目的 通过构建N-乙酰转移酶基因(NAA10)腺病毒表达载体,探讨其对食管癌细胞TE-1增殖、细胞周期和凋亡的影响.方法 PCR技术扩增NAA10全长编码基因,通过重组腺病毒表达系统将其克隆入pShuttle-IRES-hrGFP-1穿梭载体,重组腺病毒表达载体并包装腺病毒颗粒Ad-NAA10.将携带人NAA10基因的腺病毒感染食管癌细胞TE-1,Western blot检测NAA10蛋白的表达,CCK-8检测其对TE-1细胞增殖的影响,碘化丙啶(PI)染色检测其对TE-1细胞周期的影响,Hoechst/PI双染检测其对TE-1细胞凋亡的影响.结果 酶切鉴定和测序证实NAA10腺病毒表达载体构建成功,腺病毒颗粒Ad-NAA10能在TE-1细胞中正常表达;NAA10可以抑制TE-1细胞的增值,影响细胞周期分布,促进细胞凋亡.结论 NAA10通过G1期阻滞和诱导凋亡从而抑制食管癌细胞的增殖,为进一步确定食管癌特异性生物标志物及探讨食管癌发病机制奠定基础.     

基于N-乙酰转移酶研究槲皮素对大鼠体内异烟肼代谢的影响

目的 基于N-乙酰转移酶(NAT)的表达及活性检测,研究槲皮素对大鼠体内异烟肼(INH)代谢及药动学特征影响.方法 雄性Wistar大鼠单独灌胃给予INH(60 mg/kg)或槲皮素(50 mg/kg)联合INH(60 mg/kg).分别于给药后不同时间收集血清,应用液质联用技术测定血清中INH及其代谢物乙酰异烟肼(A...     

N-乙酰基转移酶2(NAT2)基因多态性与肺癌易感性关系的Meta分析

目的探讨分析NAT2多态性与肺癌易感性的关系。方法在中英文数据库中按照统一的检索策略,全面检索至2013年8月1日有关NAT2多态性与肺癌风险关系的观察性研究相关文献。按照纳入与排除标准选择文献、提取资料和评价质量进行Meta分析。结果共纳入23篇文献,分别来自15个国家,累计肺癌病例4 425人,对照病例6 663人。结论本Meta分析结果表明:NAT2基因多态性与肺癌易感性之间未见显著关联。     

药物代谢酶遗传多态性对药物神经毒性的影响

神经毒性是药物常见的毒性反应之一。神经系统对药物引起的损害尤其敏感,药物引起神经系统结构和功能的微小改变即可表现出严重的精神或行为异常,因此药物引起的神经毒性越来越得到人们的关注。药物引起的神经毒性存在个体差异,其中遗传因素对这种差异的产生发挥重要作用。药物代谢酶影响药物体内的生物转化过程,因此代谢酶的遗传多态性在一定程度上决定了不同个体对药物神经毒性的易感性。本篇综述将着重探讨药物代谢酶中的细胞色素P450酶、谷胱甘肽转移酶和N-乙酰转移酶遗传多态性对药物神经毒性易感性的影响。     

N-乙酰半胱氨酸对小鼠免疫性肝损伤的影响

目的研究N-乙酰半胱氨酸(NAC)对卡介苗(BCG)与细菌脂多糖(LPS)引起小鼠免疫性肝损伤的影响。方法建立BCG/LPS引起的小鼠免疫性肝损伤模型。采用两种处理方式给予NAC:方式A,于LPS处理前4h和15min分别经腹腔注射给予NAC(预处理);方式B,于LPS处理后0h和4h分别经腹腔注射NAC(后处理)。LPS处理后8h剖杀动物,取血和肝脏,并检测血清丙氨酸氨基转移酶(ALT)活性与一氧化氮(NO)水平、肝脏组织谷胱甘肽(GSH)与丙二醛(MDA)含量以及肿瘤坏死因子α(TNF-α) mRNA表达水平。结果与模型组比较,NAC预处理组小鼠血清ALT活性下降,肝脏TNF-α mRNA表达明显减少,而体内NO生成和肝脏脂质过氧化水平无改变;NAC后处理组与模型组相比,小鼠死亡率升高,血清NO生成增加,肝脏GSH含量进一步下降,而小鼠血清ALT活性未见明显改变。结论NAC对小鼠免疫性肝损伤有双重效应,NAC预处理对抗BCG/LPS引起的小鼠免疫性肝脏损伤,NAC后处理加重BCG/LPS引起的氧化应激并升高动物死亡率。     

N-乙酰半胱氨酸对糖尿病模型小鼠氧化应激的影响研究

目的:探讨N-乙酰半胱氨酸(NAC)对糖尿病模型小鼠氧化应激的影响。方法:取小鼠腹腔注射链脲佐菌素建立糖尿病模型,建模成功8周后随机分为非治疗组和NAC治疗组(200mg·kg-1.d-1),每组6只,腹腔注射相应药物,每日1次,连续4周,另设正常对照组进行比较。检测各组小鼠给药前后体重、血糖水平及给药后尿液中脂质过氧化标志物8-异前列腺素(8-Isoprostane)浓度。结果:与正常对照组比较,非治疗组和NAC治疗组小鼠给药前后体重均明显降低,血糖均明显升高(P<0.001),但2组间比较无显著性差异;与非治疗组比较,NAC治疗组小鼠尿液中8-Isoprostane浓度明显降低(P<0.01),且与正常对照组比较无显著性差异。结论:NAC可有效改善糖尿病模型小鼠的氧化应激状态。     

不同来源的N-乙酰神经氨酸裂合酶的特性及在大肠埃希菌中的表达

综述了N-乙酰神经氨酸裂合酶的特性、应用及反应机理，对不同来源的N-乙酰神经氨酸裂合酶进行了比较。简要阐述N-乙酰神经氨酸裂合酶在大肠埃希菌中的克隆表达及其纯化。     

N-乙酰半胱氨酸防治脓毒症的研究进展

脓毒症是临床常见危重症,病死率高,其发病机制复杂,目前认为氧化应激参与其发病过程,N-乙酰半胱氨酸作为一种巯基供给体,具有抗氧化损伤,抗炎等作用,日益受到重视。现就脓毒症的发病机制、N-乙酰半胱氨酸防治脓毒症的机制及其在动物实验和临床应用中的情况作一介绍。     

不同肿瘤细胞株N-乙酰氨基半乳糖转移酶2的差异表达

O-聚糖在肿瘤细胞中其结构会发生异常,并与癌细胞的表型及生物学特性密切相关。多肽N-乙酰氨基半乳糖转移酶2（pp-GalNAcT2）催化 O-聚糖合成的第一步。本文研究其在不同肿瘤细中的差异表达,以探索其在肿瘤发生、发展中的作用。     

芳香胺N-乙酰化转移酶的研究进展

芳香胺N-乙酰化转移酶(arylamineN-acetyltransferase,NATs)为Ⅱ相药物代谢酶,在药物代谢和毒物解毒方面起着重要作用,是一种很有前途的药物作用新靶点。目前对其的研究主要集中在酶的晶体结构上和在不同物种、人种及相同人种、物种的多态性研究方面,而对其本身的生理活性和药理作用方面的研究相对来说还比较薄弱。该文从NATs的结构、NAT致癌的药理学机制、NATs的内源性作用、NATs失活剂/抑制剂、NATs的替代品、动力学研究、NAT酶的多态性与疾病、NAT酶活性测定方法等几个方面进行一个较为全面的阐述。     

Study of ABCB1 polymorphism frequency in breast cancer patients from Poland

BackgroundThe accumulation of mutagenic substances in the human body may result in DNA metabolism disruption followed by carcinogenesis. As a consequence of mutations in the genes coding for transmembrane protein pumps, the intracellular concentration of xenobiotics may significantly increase. This, in turn, may provoke altered risk for cancer development. The gene known to be the most relevant in the transport of numerous compounds is ABCB1 (also known as MDR1). Numerous mutations and polymorphisms that affect the encoded protein's (PgP) function were identified in this gene.The aim of the study was to define the frequency of 2677G > A,T and 3435C > T polymorphisms in a population of Polish breast cancer patients and to estimate their contribution to cancer development.MethodsThe polymorphism frequency analysis (209 patients vs. 202 control subjects) was performed either by allele-specific amplification (2677G > A,T) or by restriction fragment length polymorphism (RFLP) using the SAU3AI restriction enzyme (3435C > T) followed by verification with hybridization probe assays in a Real-Time system and sequencing.ResultsIn the control group the frequency of individual 2677 genotypes was: wild homozygous GG = 34%, heterozygous G/T or G/A = 52.5% and variant homozygous AA or TT = 13.5%, while the genotype frequency in the group of studied patients was 43.5, 44.5 and 12%, respectively. In the control group, the frequency of individual 3435 genotypes was: CC = 25.4%, CT = 50.2%, TT = 24.4%, while the genotype frequency in the group of studied patients was 23, 46 and 31%, respectively.ConclusionsThus, no significant differences in the studied polymorphism frequencies were observed. It is then suggested that the studied polymorphisms, although probably good candidates in other tissue cancer types, might not be good predictive factors in breast cancer risk or development in Caucasians.     

Genetic polymorphisms of human UDP-glucuronosyltransferase (UGT) genes and cancer risk

Identification of genetic polymorphisms that contribute to the risk of developing cancers is important for cancer prevention. The most recent human genome GRCh38/hg38 assembly (2013) reveals thousands of genetic polymorphisms in human uridine diphosphoglucuronosyltransferase (UGT) genes. Among these, a large number of polymorphisms at the UGT1A and UGT2B genes have been shown to modulate UGT gene promoter activity or enzymatic activity. Glucuronidation plays an important role in the metabolism and clearance of endogenous and exogenous carcinogenic compounds, and this reaction is primarily catalyzed by the UGT1A and UGT2B enzymes. Therefore, it has long been hypothesized that UGT polymorphisms that reduce the capacity to glucuronidate carcinogens and other types of cancer-promoting molecules (e.g. sex hormones) are associated with an increased risk of developing cancers. A large number of case-control studies have investigated this hypothesis and these studies identified numerous UGT polymorphisms in UGT1A and UGT2B genes as genetic risk factors for a wide variety of cancers, including bladder, breast, colorectal, endometrial, esophageal, head and neck, liver, lung, prostate, and thyroid. These UGT polymorphisms may be cancer causative polymorphisms, or be linked to as yet undefined causative polymorphisms, either in UGT genes or neighboring genes. This article presents a comprehensive review of these case-control studies, discusses current areas of uncertainty, and highlights future research directions in this field.     

维生素D受体基因多态性位点rs7975232与肺癌发病风险的相关性

目的探讨维生素D受体基因rs7975232位点与汉族人群肺癌发病风险的相关性。方法用直接测序法对72例肺癌患者及67名健康对照者进行单核苷酸多态性位点检测,采用ABI3700XL基因分析仪测序。结果维生素D受体基因rs7975232位点等位基因A携带者肺癌发病风险明显低于等位基因C携带者[比值比（OR）=0．501,95％置信区间（CI）为0．273～0．920,P=0．026]。rs7975232位点可能与鳞癌发病相关（等位基因之比：OR=0．274,95％CI为0．087～0．861,P=0．027;显性基因模型：OR=0．269,95％C,为0．074—0．971,P=0．045）。结论维生素D受体基因rs7975232位点与肺癌发病相关。     

Genetic analysis of N-acetyltransferase polymorphism in a Chinese population

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Oxidative polymorphism of debrisoquine is not related to human colo-rectal cancer

Summary The oxidative polymorphism of debrisoquine (DBQ) has been determined in 89 patients with colo-rectal cancer and in 556 normal control subjects. Four patients and 34 controls, with a metabolic ratio >12.6, were classified as poor metabolisers of DBQ (n.s.).No difference was found in the distribution of the frequencies of the MR of DBQ between patients and controls.It is concluded that polymorphic oxidation of DBQ is not related to the risk of developing colo-rectal cancer in human beings.     

N-acetyltransferase 2 (Nat2) polymorphism in the sand rat Psammomys obesus

Human arylamine N-acetyltransferase 1 (NAT1) and its homologue in rodents (Nat2) are polymorphic xenobiotic metabolizing enzymes and also seem to play a role in endogenous metabolism. NAT1 and Nat2 polymorphism was associated to cancers under xenobiotic procarcinogens metabolism as well as under endogenous substrate metabolism. This study investigated the p-aminobenzoic acid (PABA) -Nat2 catalytic activity and its polymorphism in liver homogenates of adult sand rats Psammomys obesus Cretzschmar, 1828. These Saharian sand rats develop high incidence of spontaneous cancers under standard laboratory diet. The average value of PABA-Nat2 specific activity tested in nine sand rats was significant (2.96?±?2.16 nmoles/min/mg). The N-acetylation exhibited a bimodal distribution. There was a significant difference (p?<?0.01) between PABA-Nat2 activity in the fast acetylators group (4.10?±?1.67 nmol/min/mg) and slow acetylators group (0.7?±?0.27 nmol/min/mg). The percentage of the fast acetylator group was 66.66%. These results support the presence of Nat2 polymorphism in the liver of the strain sand rats Psammomys obesus. This strain is useful for investigating the role of Nat2 polymorphisms in susceptibility to cancers related to arylamine carcinogen exposures as well as to endogenous substrate metabolism.     

TSH-β gene polymorphism in Saudi patients with thyroid cancer: A case-control study

BackgroundThe role of thyroid-stimulating hormone in the pathogenesis of thyroid cancer is not yet fully explored. This study aimed to evaluate the role of the TSH-β polymorphism in thyroid cancer in a Saudi cohort.MethodsA prospective case-control study was conducted on 507 patients with differentiated thyroid carcinoma and compared them with 560 controls of Saudi origin. The association of two variants, the rs201857310, and rs7530810, in the TSH-β gene with thyroid cancer risk as well as thyroxine dose, were evaluated.ResultsThe rs201857310_A > G [OR: 0.50 (95 % CI: 0.35–0.71); P < 0.0001] was strongly associated with thyroid cancer. The multivariable analysis adjusted the effect of possible confounders (age, sex, body mass index, and smoking). Multivariable analysis elucidated that the rs201857310 maintained its significant association with the disease [OR: 0.47 (95 % CI: 0.32–0.68); P < 0.0001]. There was no significant association between the other rs7530810 variant and the disease. There was no association between any of the variants and the thyroxine dose requirement (P = 0.79 and 0.73).ConclusionsOur findings indicate that the TSH-β gene could have a role in the pathogenesis of differentiated thyroid carcinoma in the Saudi population.     

Increased cancer risk in patients with periodontitis

Background: Previous studies have noted a possible association between periodontal diseases and the risk of various cancers. We assessed cancer risk in a cohort of patients with moderate to severe periodontitis.

Methods: Patients diagnosed with moderate to severe periodontitis by a periodontist between 2001 and 2010 were identified from the hospital registry. Patients younger than 35 years of age or with a prior cancer diagnosis were excluded. The age- and gender-standardized incidence rates (SIR) were calculated by dividing the number of observed cases by the number of expected cases from Turkish National Cancer Registry 2013 data.

Results: A total of 280 patients were included (median age 49.6, 54% female). Median follow-up was 12 years. Twenty-five new cancer cases were observed. Patients with periodontitis had 77% increased risk of cancer (SIR 1.77, 95% CI 1.17–2.58, p?=?.004). Women with periodontitis had significantly higher risk of breast cancer (SIR 2.40, 95% CI 0.88–5.33) and men with periodontitis had significantly higher risk of prostate cancer (SIR 3.75, 95% CI 0.95–10.21) and hematological cancers (SIR 6.97, 95% CI 1.77–18.98).

Conclusion: Although showing a causal association necessitates further investigation, our results support the idea that periodontitis might be associated with increased cancer risk, particularly with hematological, breast and prostate cancers.     

乙醛脱氢酶2基因多态性与癌症的关系及药物治疗的研究进展

乙醛脱氢酶2(ALDH2)是人类肝脏中氧化乙醛的关键酶,能将乙醛转化为乙酸,在酒精的代谢过程中,ALDH2发挥着重要的解毒作用.当ALDH2的酶活性受其编码基因ALDH2多态性的影响而致酶活性下降时会导致乙醛在体内蓄积,增加癌症风险.越来越多的研究表明ALDH2的基因多态性与肿瘤的发生、发展密切相关.就ALDH2的基因...