乙醇和乙醛脱氢酶基因多态与食道癌易感性

目的 研究乙醇脱氢酶2(ADH2)和乙醛脱氧酶2(ALDH2)基因多态与食道癌易感性.方法 对江苏省泰兴市221例食道癌新发病例和191名对照的饮酒习惯等因素进行调查,采用PCR和变性高效液相色谱法(DHPLC)检测ADH2和ALDH2基因型.结果 (1)与携带ALDH2 G/G基因型者相比,携带ALDH2A/A(OR=5.69,95%CI:2.51～12.18)和ALDH2 G/A(OR=1.70,95%CI:1.08～2.68)基因型者患食道癌危险性明显增加,以携带ALDH2A/A的饮酒者最为显著(OR=8.63,95%CI:2.07～35.95).(2)无论是否饮酒,携带不同ADH2基因型者之间患食道癌的风险差异均无统计学意义.(3)携带ALDH2 A/A或G/A基因型者,不论同时携带何种ADH2基因型患食道癌的风险均显著增加,且作用效应为ALDH2 A/A≥G/A.(4)与同时携带ALDH2 G/G和ADH2 A/A的不饮酒者相比,同时携带ALDH2 G/A或A/A和ADH2 G/A或G/G的饮酒者,患食道癌危险性OR值高达8.36(95%CI:2.98～23.46).结论 饮酒及醇醛脱氢酶基因多态与食道癌的联系主要与ALDH2有关;携带ALDH2A/A和G/A者减少酒精消耗量,有助于降低患食道癌危险性.     

Effective health care: management of head and neck cancers

The management of head and neck cancer, published in a recent issue of Effective Health Care, is reviewed.     

HPV与头颈部鳞状细胞癌预后关系Meta分析

头颈癌（HNC）的病因主要是烟草和酒精的暴露,在戒烟行动的号召下,吸烟相关的HNC发病率下降,人乳头瘤病毒（HPV）感染导致HNC的病例逐渐增多,尤其是发达国家,其中在美国HPV相关HNC超过宫颈癌成为HPV相关的第一大肿瘤。此外,随HPV疫苗的陆续上市,宫颈癌的研究逐渐进入后疫苗时代,HPV其他相关肿瘤,尤其是HNC成为下一研究的热点。     

Occupational exposures and head and neck cancers among Swedish construction workers

OBJECTIVES: Occupational exposures in the construction industry may increase the risk of head and neck cancers, although the epidemiologic evidence is limited by problems of low study power and inadequate adjustment for tobacco use. In an attempt to address this issue, the relationship between selected occupational exposures and head and neck cancer risk was investigated using data from a large cohort of Swedish construction workers. METHODS: Altogether 510 squamous cell carcinomas of the head and neck (171 in the oral cavity, 112 in the pharynx, 227 in the larynx) were identified during 1971-2001 among 307 799 male workers in the Swedish construction industry. Exposure to diesel exhaust, asbestos, organic solvents, metal dust, asphalt, wood dust, stone dust, mineral wool, and cement dust was assessed using a semi-quantitative job-exposure matrix. Rate ratios (RR) and 95% confidence intervals (95% CI) were calculated for head and neck cancers in relation to occupational exposure, using Poisson regression with adjustment for age and smoking status. RESULTS: Asbestos exposure was related to an increased laryngeal cancer incidence (RR 1.9, 95% CI 1.2-3.1). Excesses of pharyngeal cancer were observed among workers exposed to cement dust (RR 1.9, 95% CI 1.2-3.1). No occupational exposures were associated with oral cavity cancer. These findings did not materially change upon additional adjustment for cigarette pack-years. CONCLUSIONS: These findings offer further evidence that asbestos increases the risk of laryngeal cancer. The observation of a positive association between cement dust exposure and pharyngeal cancer warrants further investigation.     

Genetic polymorphisms of XRCC1, alcohol consumption, and the risk of colorectal cancer in Japan

Background

X-ray cross-complementing group 1 (XRCC1) polymorphisms affect DNA repair capacity and may therefore be of importance in colorectal carcinogenesis. Alcohol consumption, an important risk factor for colorectal cancer, may induce carcinogenesis through DNA damage caused by the toxic effects of alcohol or its metabolites. Therefore, we examined the associations of XRCC1 Arg399Gln, Arg280His, and Arg194Trp polymorphisms with colorectal cancer and the impact of the association between alcohol consumption and colorectal cancer risk.

Methods

This case-control study in Fukuoka, Japan including 685 cases and 778 controls. The cases were incident patients with histologically confirmed colorectal adenocarcinoma. The controls were randomly selected community subjects.

Results

The XRCC1 399Gln/Gln genotype was significantly associated with colorectal cancer risk (adjusted odds ratio [OR] 1.57, 95% CI 1.01–2.42; relative to 399Arg/Arg genotype). The association was strongest in individuals with high alcohol consumption. The Arg280His polymorphism modified the association between alcohol consumption and colorectal cancer risk (interaction P = 0.049). The OR of colorectal cancer in individuals with the 280His allele was 0.45 (95% CI 0.26–0.78) as compared with the 280Arg/Arg genotype limited to the 399Gln allele (interaction P = 0.001). The adjusted ORs for 399Gln/Gln-280Arg/Arg-194Arg/Arg and 399Arg/Gln-280Arg/Arg-194Arg/Trp were 1.71 (95% CI 1.02–2.87) and 1.57 (95% CI 1.05–2.33), respectively, with 399Arg/Arg-280Arg/Arg-194Arg/Arg as reference (interaction P = 0.418).

Conclusions

The findings are additional evidence that individuals with the XRCC1 399Gln/Gln genotype have an increased risk of colorectal cancer, and that XRCC1 polymorphisms have an important role in colorectal cancer risk associated with alcohol consumption or gene-gene interaction.Key words: XRCC1 polymorphisms, alcohol consumption, colorectal cancer     

Molecular abnormality and cDNA cloning of human aldehyde dehydrogenases

Usual human livers contain two major ALDH isozymes, i.e., cytosolic ALDH1 and mitochondrial ALDH2, while approximately 50% of Orientals are "atypical" and have only the ALDH1 and are missing the ALDH2. Instead, the atypical livers contain an enzymatically inactive but immunologically cross-reactive material (CRM) corresponding to the ALDH2 component. Some Orientals are found to be atypical also in the ALDH1 locus, i.e., they are missing the enzymatically active ALDH1 but contain a large amount of CRM corresponding to the ALDH1 component. cDNA for ALDH1 and that for ALDH2 were cloned and their nucleotide sequences were determined. The amino acid sequences of ALDH1 and ALDH2 were deduced from their cDNA sequences. The molecular abnormality of the inactive ALDH2(2) is found to be the substitution of Glu at the 14th position from the COOH-terminal of the protein by Lys which resulted from G----A transition in the gene.     

ADH1B与ALDH-2基因多态性与中国人群食管癌发病风险的Meta分析

目的探讨中国人乙醇脱氢酶1B(ADH1B)和乙醛脱氢酶-2(ALDH-2)的基因多态性与食管癌发病风险的关系。方法检索中外文数据库,获得有关ADH1B和ALDH-2位点的多态性与食管癌发病风险的病例-对照研究资料,对各位点以及与饮酒的交互作用进行Meta分析,得到合并的OR值及其95%CI。结果等位基因ADH1B*1和ALDH-2*2可增加食管癌的发病风险。基因型ADH1B*1/*2和ADH1B*1/*1的OR值分别为1.24(95%CI 1.10-1.41)和3.05(95%CI 1.94-4.77);基因型ALDH-2*1/*2和ALDH-2*2/*2的OR值分别为1.6(95%CI 1.01-2.03)和0.77(95%CI 0.28-2.09)。在饮酒人群中,与基因型ADH1B*2/*2相比,ADH1B*1/*2+*2/*2的OR=3.13(95%CI 2.17-4.51);与基因型ALDH-2*1/*1相比,ALDH-2*1/*2+*2/*2的OR=4.12(95%CI 1.98-8.56)。结论在中国人群中,等位基因ADH1B*1和ALDH-2*2均能增加食管癌患病的风险,且饮酒可以增加这一风险。     

Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol

Acetaminophen is one of the most widely used over-the-counter analgesic, antipyretic medications. Use of acetaminophen and alcohol are commonly associated. Previous studies showed that acetaminophen might affect bioavailability of ethanol by inhibiting gastric alcohol dehydrogenase (ADH). However, potential inhibitions by acetaminophen of first-pass metabolism (FPM) of ethanol, catalyzed by the human ADH family and by relevant aldehyde dehydrogenase (ALDH) isozymes, remain undefined. ADH and ALDH both exhibit racially distinct allozymes and tissue-specific distribution of isozymes, and are principal enzymes responsible for ethanol metabolism in humans. In this study, we investigated acetaminophen inhibition of ethanol oxidation with recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and inhibition of acetaldehyde oxidation with recombinant human ALDH1A1 and ALDH2. The investigations were done at near physiological pH 7.5 and with a cytoplasmic coenzyme concentration of 0.5 mm NAD⁺. Acetaminophen acted as a noncompetitive inhibitor for ADH enzymes, with the slope inhibition constants (K_is) ranging from 0.90 mm (ADH2) to 20 mm (ADH1A), and the intercept inhibition constants (K_ii) ranging from 1.4 mm (ADH1C allozymes) to 19 mm (ADH1A). Acetaminophen exhibited noncompetitive inhibition for ALDH2 (K_is = 3.0 mm and K_ii = 2.2 mm), but competitive inhibition for ALDH1A1 (K_is = 0.96 mm). The metabolic interactions between acetaminophen and ethanol/acetaldehyde were assessed by computer simulation using inhibition equations and the determined kinetic constants. At therapeutic to subtoxic plasma levels of acetaminophen (i.e., 0.2–0.5 mm) and physiologically relevant concentrations of ethanol (10 mm) and acetaldehyde (10 μm) in target tissues, acetaminophen could inhibit ADH1C allozymes (12–26%) and ADH2 (14–28%) in the liver and small intestine, ADH4 (15–31%) in the stomach, and ALDH1A1 (16–33%) and ALDH2 (8.3–19%) in all 3 tissues. The results suggest that inhibition by acetaminophen of hepatic and gastrointestinal FPM of ethanol through ADH and ALDH pathways might become significant at higher, subtoxic levels of acetaminophen.     

Genetic polymorphisms and chromosome damage.

Genetic polymorphisms that affect xenobiotic metabolism or cellular response to DNA damage can modulate individual sensitivity to genotoxins. Information on the effects of such polymorphisms on the level of chromosome damage may facilitate the identification of risk groups and increase the sensitivity of cytogenetic endpoints as biomarkers of genotoxic exposure and effect. Glutathione S-transferase M1 (GSTM1) is an important detoxification enzyme which, due to a homozygous gene deletion (null genotype), is lacking from about 50% of Caucasians. A higher level of DNA adducts and chromosome damage has been detected in lymphocytes of tobacco smokers and bus drivers who lack the GSTM1 gene. Other polymorphic glutathione S-transferases include GSTM3, GSTP1, and GSTT1. The GSTT1 null genotype (10-20% of Caucasians) has been associated with an increased "baseline" level of sister chromatid exchanges (SCEs) in lymphocytes. N-acetyltransferase 2 (NAT2), metabolizing xenobiotics with primary aromatic amine and hydrazine structures, is another important polymorphic phase II enzyme. Subjects having the NAT2 slow acetylator genotype appear to show an increased baseline frequency of lymphocyte CAs in the absence of identified environmental exposure. Besides human biomonitoring studies, genetic polymorphisms may be important in explaining individual variation in genotoxic response observed in genetic toxicology tests with human cells. Several studies have suggested that blood cultures from GSTT1 null and GSTM1 null individuals have increased in vitro sensitivity to various genotoxins. The best-known example is probably the diepoxybutane sensitivity of GSTT1 null donors. Recently discovered polymorphisms affecting DNA repair may be expected to be of special importance in modulating genotoxic effects; the first available studies have suggested that the exon 10 Arg399Gln polymorphism of XRCC1 gene (X-ray repair cross-complementing group 1) could affect individual genotoxic response. In conclusion, the genetic polymorphism of GSTM1 influences the frequency of chromosome damage in exposed humans, while that of GSTT1 and NAT2 affect the "baseline" level of such damage. Both GSTM1 and GSTT1 genotypes may shape the in vitro genotoxic response of human lymphocytes. The significance of DNA repair polymorphisms is presently unclear.     

Tumor cytokinetic response to total parenteral nutrition in patients with head and neck cancers

Refeeding of patients with malignant tumors may induce tumor-cell DNA synthesis. The present study was aimed at evaluating whether induction of altered cell-cycle kinetics could be induced by intravenous total parenteral nutrition (TPN) in tumor biopsies from head and neck cancers. Nine malnourished patients with squamous cell carcinoma in the head-and-neck area were investigated before and after 5-7 d of continuous TPN. Tumor biopsies were taken in both fasted and fed states for determination of 1) ornithine decarboxylase (ODC) activity, which is rate limiting for polyamine synthesis; 2) flow-cytometric-DNA-distribution measurements; and 3) the fraction of proliferating cells expressed as immunohistochemical reactivity with the monoclonal antibody Ki-67. The histopathological differentiation, the fraction of aneuploidic cells, ODC activity, and Ki-67 reactivity were not significantly related to each other, although the number of aneuploidic cells in replicative phases correlated with the number of cells expressing the Ki-67 antigen (r = 0.86, P less than 0.01). Tumor cytokinetics showed no evidence of being changed by TPN administration.