Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sixty-three male cigarette smokers were entered into a cross-sectional study to determine whether inverse associations existed between polycyclic aromatic hydrocarbon (PAH)-DNA adduct levels and intake/serum levels of vitamin A, vitamin C and vitamin E. Associations between PAH-DNA adducts and intakes of carotene, as well as serum levels of beta-carotene, were also determined. Fasting blood samples were collected for assays of PAH-DNA adducts in circulating mononuclear cells, plasma cotinine and serum levels of vitamin A, beta-carotene, vitamin C and vitamin E. Since genetic deficiency in the detoxifying enzyme glutathione S-transferase M1 (GSTM1) has been associated with increased risk of lung cancer, GSTM1 genotype was also determined. Analysis of PAH-DNA adducts by competitive enzyme-linked immunosorbent assay (ELISA) indicated that 70% of the subjects had detectable adducts, with a mean of 4.38 adducts/10(8) nucleotides (range 1.00-24.1/10(8)). Pearson's method was utilized to determine whether any associations existed between the various host variables and PAH-DNA adducts. Previously, no significant associations were found between PAH-DNA adducts and cigarettes smoked/day, pack-years, daily/life-time tar exposures or plasma cotinine levels (Santella et al., Carcinogenesis, 13, 2041-2045, 1992). PAH-DNA adducts were inversely associated with serum cholesterol-adjusted vitamin E levels (r = -0.25, P < or = 0.05) and with smoking-adjusted vitamin C serum levels (r = -0.22, P < or = 0.09). Stratification by GSTM1 genotype indicated that these associations were limited to subjects with the null genotype. The relationship between adducts and serum cholesterol-adjusted vitamin E was significant in those of the null genotype (r = -0.38, P < or = 0.04), but not in those with the gene present (r = -0.12, P = 0.5). Similarly, for smoking-adjusted vitamin C, the relationship with adducts was stronger in subjects with the null genotype (r = -0.35, P < or = 0.06) than in those with GSTM1 present (r = -0.05, P = 0.77). These results are consistent with findings of prior epidemiological studies identifying significant inverse associations between anti-oxidant micronutrient status or GSTM1 genotype and the incidence of lung cancer. Additional studies should be conducted to confirm a possible role for vitamin E in PAH-DNA adduct formation and to explore further the possible roles of vitamin A, beta-carotene and vitamin C in modulating adduct formation and lung cancer risk.
Carcinogenesis 1994 Nov
PMID:Polycyclic aromatic hydrocarbon-DNA adducts in smokers and their relationship to micronutrient levels and the glutathione-S-transferase M1 genotype. 795 90

The frequency of the GSTM1 0 polymorphism at the glutathione S-transferase M1 locus has been determined in controls and patients with pituitary adenomas by using the polymerase chain reaction to amplify genomic DNA in the exon 4-5 region of the gene. The frequency of the genotype in patients with prolactinomas, non-functional adenomas, corticotrophinomas and somatotrophinomas varied between 52-67% compared with 44% in the controls. In the patients with prolactinomas the frequency of the genotype (67%) was significantly greater than in controls with odds ratio analysis indicating that GSTM1 0 individuals have a 2.56-fold greater risk of developing this adenoma.
Carcinogenesis 1993 Apr
PMID:The glutathione S-transferases: polymerase chain reaction studies on the frequency of the GSTM1 0 genotype in patients with pituitary adenomas. 847 15

Cigarette smoking is the major cause of bladder cancer in men in the United States, and the arylamines contained in cigarettes smoke, including 4-amino-biphenyl (4-ABP), are believed to play an important role in the induction of bladder cancer among smokers. N-acetylation, which is catalyzed by the genetically controlled hepatic N-acetyltransferase enzyme displaying two phenotypes (slow versus rapid), is a detoxification pathway for arylamines with regard to bladder carcinogenesis. In Los Angeles, CA, non-Hispanic white (white), black, and Asian males have comparable smoking habits and yet dramatically different risks of bladder cancer (31 of 100,000 in whites, 16 of 100,000 in blacks, and 13 of 100,000 in Chinese and Japanese). Previously, we have demonstrated that the prevalence of slow acetylators (the high-risk phenotype) was highest in whites (54%), intermediate in blacks (34%), and lowest in Asians (14%). We also showed that mean 3- and 4-ABP hemoglobin adduct levels were significantly higher in cigarette smokers relative to nonsmokers, and that the level increased with increasing number of cigarettes smoke/day. Most importantly, slow acetylators consistently exhibited higher mean levels of ABP hemoglobin adducts relative to rapid acetylators, regardless of race and level of cigarette smoking. We assessed 151 residents of Los Angeles County (CA) who were either white, black, or Asian (Chinese or Japanese) and over the age of 30 years for their glutathione S-transferase M1 (GSTM1) genotype (null versus non-null), acetylator phenotype (slow versus rapid), levels of 3- and 4-ABP hemoglobin adducts, and current use of tobacco products. Whites (27%) had the highest prevalence of the highest risk profile (slow acetylator, GSTM1 null), followed by blacks (15%) and Asians (2.7%), and the difference was statistically significant (P = 0.006). Whites also had less than one-half the prevalence of the "protective" profile (rapid acetylator, GSTM1 non-null) relative to blacks and Asians (23 versus 57%; P = 0.0001). Regardless of race and level of cigarette smoking, mean levels of 3- and 4-ABP hemoglobin adducts were higher in subjects possessing the higher risk (GSTM1/acetylator profile. Mean level of 4-ABP hemoglobin adduct (adjusting for race, cigarette smoking, and acetylator phenotype) was significantly higher in subjects possessing the GSTM1-null versus GSTM1-non-null genotype (46.5 versus 36.0 pg/g Hb; P = 0.037). The comparable difference in mean levels of 3-ABP hemoglobin adduct was borderline significant (1.6 versus 1.1 pg/g Hb; P = 0.07). Thus, our results suggest that GSTM1 is involved in the detoxification of 3- and 4-ABP and may contribute to the racial variation in bladder cancer incidence among white, black, and Asian males in Los Angeles, CA.
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PMID:Glutathione S-transferase M1 genotype affects aminobiphenyl-hemoglobin adduct levels in white, black and Asian smokers and nonsmokers. 863 58

There has been increasing interest in the interaction of genetic susceptibility and xenobiotic exposures in cancer etiology. Study of gene-environment interactions may increase our ability to characterize relatively low population risks if a substantial proportion of the population cancer burden is attributed to high risk among a smaller group of genetically susceptible members. Further, these studies may provide insight into the mechanism of carcinogenesis, which can help establish the biologic plausibility of an exposure-cancer relationship. Biologic processes important in tumorigenesis that exhibit substantial interindividual differences may function as susceptibility factors. Potential examples include polymorphic enzymes, which activate and detoxify procarcinogens and carcinogens (e.g., certain P450 enzymes, N-acetyltransferase [NAT2], glutathione S-transferase M1), and variation in the capacity to repair DNA. Biologic assays are now available to evaluate many of these functions at the DNA and phenotype level and can be readily incorporated into studies of cancer etiology.
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PMID:Using biomarkers of genetic susceptibility to enhance the study of cancer etiology. 874 1

Glutathione transferases are involved in the detoxification of many zenobiotica involved in the etiology of cancer. To investigate the role of the glutathione S-transferase M1 deletion (GSTM1*0/0) in bladder carcinogenesis, the polymerase chain reaction was used to determine the GSTM1 genotypes of cancer patients (n = 234) and hospital controls (n = 202). Overall, the proportion of GSTM1*0/0 in the case group was 57%, compared to 50% in the control group giving an odds ratio (OR) of 1.33, (0.91-1.94; 95% confidence interval (CI)). Dividing the bladder cancer group into incident (n = 87) and surviving case groups (n = 147), a modest association between the GSTM1*0/0 genotype and bladder cancer was found in the surviving group, whereas, in the incident group no association was found. Logistic regression analysis of the incident cases, adjusting for age, gender, and cigarette smoking, revealed ORs of 1.12 (0.61-2.08) and 0.74 (0.33-1.73) for the malignant and benign tumours, respectively. The corresponding adjusted ORs for the surviving cases were 1.81 (1.04-3.13) for benign and 1.43 (0.80-2.56) for malignant tumours. Thus, in this study, the GSTM1 deletion is not a risk factor for the development of bladder cancer, but may be related to the survival of the bladder cancer patients. This finding is very important for the design of case-control studies in general, and for the interpretation of existing data.
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PMID:Glutathione S-transferase mu as a risk factor in bladder tumours. 880 65

Genes coding for the glutathione S-transferase M1 (GSTM1) and Theta 1 (GSTT1) proteins are polymorphic in humans and these genes are absent, or homozygous null, in 10-60% of different ethnic populations. These enzymes catalyze the conjugation of glutathione to numerous carcinogenic chemicals and previous epidemiologic studies have associated the null genotypes of these GST genes with higher risk of cancer. In this study the frequency of GSTM1 and GSTT1 null genotypes was determined in Japanese patients with gastric adenocarcinoma and colorectal adenocarcinoma and compared to frequencies determined in a community-based control group. The frequency of the null GSTM1 genotype in patients with gastric adenocarcinoma (56.8%) showed a statistically significant increase compared to the control group frequency (43.6%) (odds ratio (OR) = 1.70; 95% CI, 1.05-2.76). The frequency of GSTM1 null individuals was also higher among all colorectal adenocarcinoma cases, but this increase did not reach statistical significance. After grouping by tumor site, the GSTM1 null genotype was a risk factor among the subgroup with distal colorectal tumors (61.1%) (OR = 2.03; 95% CI, 1.06-3.90). No consistent difference was observed between smoking patients and corresponding controls for the frequency of the GSTM1 null genotype for either cancer, although a large risk (OR = 5.76; 95% CI 1.18-28.3) was associated with the GSTM1 null genotype in the low smoking group of gastric adenocarcinoma patients. On the other hand, no statistically significant differences were observed in the frequency of null GSTT1 genotypes in gastric (47.5%) or colorectal (48.5%) adenocarcinoma patients when compared with the control population (44.4%). These results suggest that the GSTM1 null genotype may be associated with susceptibility to gastric adenocarcinoma and distal colorectal adenocarcinoma in Japanese; however, the associations observed were relatively weak and additional studies will be needed to confirm these findings.
Carcinogenesis 1996 Sep
PMID:Glutathione S-transferase M1 (GSTM1) and T1 (GSTT1) genetic polymorphism and susceptibility to gastric and colorectal adenocarcinoma. 882 6

Prior epidemiological evidence suggests that genes controlling the metabolism of carcinogens and antioxidant/nutritional status are associated with lung cancer risk, possibly through their ability to modulate DNA damage by carcinogens. We performed a cross-sectional analysis of 159 heavy smokers from a cohort of subjects enrolled in a smoking cessation program. A total of 159 blood samples were analyzed to determine the relative contributions of genetic polymorphisms [CYP1A1 MspI and exon 7 and glutathione S-transferase M1 (GSTM1)] and plasma micronutrients to polycyclic aromatic hydrocarbon-DNA (PAH-DNA) adduct levels. DNA damage in smokers was affected by genetic polymorphisms and nutritional status. Smokers with the CYP1A1 exon 7 valine polymorphism had significantly higher (2-fold, P < or = 0.03) levels of DNA damage than those without. In parallel models, PAH-DNA adducts were inversely associated with plasma levels of retinol (beta = -0.93, P = 0.01), beta-carotene (beta = -0.18, P = 0.09), and alpha-tocopherol (beta = -0.28, P = 0.21) in 159 subjects. The association between smoking-adjusted plasma beta-carotene levels and DNA damage was only significant in those subjects lacking the GSTM1 detoxification gene (beta = -0.30, P = 0.05, n = 75). There was a statistical interaction between beta-carotene and alpha-tocopherol; when beta-carotene was low, alpha-tocopherol had a significant protective effect (beta = -0.78, P = 0.04) on adducts, but not when beta-carotene was high (beta = -0.16, P = 0.57). Plasma alpha-tocopherol was significantly correlated with beta-carotene (r = 0.36, P = 0.0005) and less strongly with retinol (r = 0.20, P = 0.0005). These results suggest that several micronutrients may act in concert to protect against DNA damage and highlight the importance of assessing overall antioxidant status. In conclusion, a subset of smokers may be at increased risk of DNA damage and possibly lung cancer due to the combined effect of low plasma micronutrients and genetic susceptibility factors. The use of biological markers to assess efficacy of interventions and to study mechanisms of micronutrients is timely given the current debate regarding the use of chemopreventive agents in high risk populations.
Carcinogenesis 1997 Mar
PMID:Contribution of genetic and nutritional factors to DNA damage in heavy smokers. 906 49

The influence of glutathione S-transferase T1 (GSTT1) genotype on the genotoxicity of 1,2-epoxy-3-butene (MEB), a metabolite of 1,3-butadiene, was assessed by the analysis of sister chromatid exchanges (SCEs) in 72-h human whole-blood lymphocyte cultures. The cultures were from 18 donors, representing both GSTT1 'positive' genotype (with at least one undeleted GSTT1 allele; GSTT1 activity present) and GSTT1 'null' genotype (homozygous deletion of the GSTT1 gene; no GSTT1 activity). As we have previously observed that allelism of glutathione S-transferase M1 (GSTM1) affects SCE induction by MEB in cultured lymphocytes, only individuals with the GSTM1 null genotype were included in this study. At 125 and 250 microM MEB (treatment at 24 h for 48 h), the mean frequencies of MEB-induced SCEs per cell (control level subtracted) were 4.5 (SD 1.8) and 8.9 (SD 1.0) for GSTT1 positive cell cultures (n = 13) and 5.3 (SD 1.2) and 12.5 (SD 1.1) for GSTT1 null cell cultures (n = 5) respectively, and the difference between the genotypes was statistically significant (P < 0.001) at the higher dose. All individual mean frequencies of SCEs induced by 250 microM MEB were higher in the GSTT1 null group (range 11.2-13.9) than in the GSTT1 positive group (range 7.2-10.8). The findings suggest that GSTT1, in addition to GSTM1, is involved in the detoxification of MEB in human whole-blood lymphocyte cultures. The deletion of the GSTT1 gene results in reduced erythrocytic detoxification capacity, thereby increasing the genotoxic effects of MEB.
Carcinogenesis 1998 Feb
PMID:Induction of sister chromatid exchange by 1,2-epoxy-3-butene in cultured human lymphocytes: influence of GSTT1 genotype. 949 93

Although cigarette smoking is one major determinant of lung carcinogenesis, not all smokers develop cancer. This phenomenon is due to individual variation in genetic susceptibility to carcinogens, nutrition, and lifestyle. Previous studies have shown that genetic polymorphism of metabolic enzymes and plasma micronutrients are associated with lung cancer risk. DNA adducts may serve as a molecular dosimeter for exposure to carcinogens. In this cross-sectional study, we analyzed the blood samples of 158 subjects to evaluate the effects of polymorphisms of cytochrome P450 1A1 (CYP1A1), glutathione S-transferase M1 (GSTM1), T (GSTT), N-acetytransferase 2 (NAT2), and aldehyde dehydrogenase 2 (ALDH2) as well as the effects of plasma beta-carotene and alpha-tocopherol on lymphocyte DNA adducts measured by 32P-postlabeling analysis. The DNA adduct level of smokers (mean +/- SD, 1.26 +/- 0.79/10(8) nucleotides) was significantly higher than that of nonsmokers (0.87 +/- 0.33, P = 0.007). Smokers with CYP1A1 minor homozygotes and GSTM1 null genotypes had a significantly higher level of DNA adducts than those without (P = 0.027 for homozygotes, P = 0.049 for heterozygotes). Smokers with NAT2 minor homozygotes also tended to have a higher DNA adduct level than those with heterozygotes and wild alleles, but the difference was not statistically significant. The DNA adduct level of smokers with ALDH2 heterozygotes was significantly higher than that of smokers with minor homozygotes (P = 0.045). When smokers were divided into "high" and "low" groups according to mean level of plasma beta-carotene or alpha-tocopherol, in the low beta-carotene group, the subjects with CYP1A1 minor homozygotes had higher DNA adduct levels than those with other CYP1A1 genotypes. Smokers with GSTT null genotype and high beta-carotene tended to have a higher DNA adduct level than those with GSTT present and high beta-carotene (P = 0.07), and those with GSTT null genotype and low beta-carotene (P = 0.07). There was weak correlation between DNA adduct level and number of cigarettes smoked per day in the low plasma beta-carotene group (r = 0.28, n = 36, p < 0.1). These results suggested that polymorphisms of CYP1A1, GSTM1, T, NAT2, and ALDH2, and plasma beta-carotene may modulate the level of DNA adducts.
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PMID:Effects of genetic polymorphism of metabolic enzymes, nutrition, and lifestyle factors on DNA adduct formation in lymphocytes. 981 Jan 47

This molecular epidemiologic case-control study of lung cancer incorporated three complementary biomarkers: the glutathione S-transferase M1 (GSTM1) null genotype, a potential marker of susceptibility, and polycyclic aromatic hydrocarbon-DNA adducts (PAH-DNA) and sister chromatid exchanges (SCE), both indicators of environmentally induced genetic damage. Associations between biomarkers and lung cancer were investigated, as were possible gene-environment interactions between the GSTM1 null genotype and tobacco smoke exposure. Subjects included 136 primary non-small cell lung cancer surgical patients and 115 controls at the Columbia Presbyterian Medical Center. Questionnaire and Tumor Registry data, pre-treatment blood samples and biomarker measurements on blood were obtained. Overall, GSTM1 null genotype was significantly associated with lung cancer [odds ratio (OR) = 2.04, 95% confidence interval (CI) = 1.13-3.68]. ORs for GSTM1 and lung cancer were significant in females (2.50, 1.09-5.72) and smokers (2.25, 1.11-4.54) and not significant in males (1.4, 0.58-3.38) and non-smokers (0.88, 0.18-4.33). However, ORs for males versus females and smokers versus non-smokers did not differ significantly. The OR for GSTM1 and lung cancer in female smokers was 3.03 (1.09-8.40), compared with 1.42 (0.53-4.06) in male smokers. In contrast to PAH-DNA adducts in leukocytes, SCE did not differ between cases and controls. Neither biomarker differed significantly between the two GSTM1 genotypes. The combined effect of elevated PAH-DNA adducts and GSTM1 genotype on case-control status (16.19, 1.2-115) appeared multiplicative. Results suggest that the effect of the GSTM1 null genotype is greatest in female smokers, which is consistent with other evidence that indicates that women are at higher risk of lung cancer than males, given equal smoking. Persons with both the GSTM1 deletion and elevated PAH-DNA adducts may represent a sensitive subpopulation with respect to carcinogens in tobacco smoke and other environmental media.
Carcinogenesis 1998 Nov
PMID:Associations between both genetic and environmental biomarkers and lung cancer: evidence of a greater risk of lung cancer in women smokers. 985 8


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