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)

1,3-Butadiene (BD) is a major commodity chemical used in the manufacture of synthetic rubber and various plastics and has been shown to be a potent animal carcinogen and a probable human carcinogen. The bioactivation of BD to reactive epoxides, and the balance between activation and detoxication of these reactive metabolites, is thought to play a critical role in the genotoxic and carcinogenic effects of BD. The detoxication of reactive BD metabolites involves enzymatic conjugation with glutathione by glutathione S-transferases (GSTs) and by hydrolysis, a reaction mediated by microsomal epoxide hydrolase (mEH). Since polymorphisms in genes of xenobiotic-metabolizing enzymes such as mEH may influence individual susceptibility to adverse health effects from BD exposure, we tested the hypothesis that the mEH Tyr113His polymorphism increases sensitivity to the genotoxic effects of BD in exposed workers. We used the autoradiographic hprt mutant lymphocyte assay as a biomarker of effect to identify genotoxicity associated with BD exposure in 49 workers from two styrene/butadiene polymer plants in Southeast Texas. Exposure to BD was assessed by collecting breathing zone air samples using passive badge dosimeters for three full 12 h work shifts 25, 20 and 14 days before blood was collected for genotyping and for the hprt assay. We genotyped the study participants for the Tyr113His polymorphism in the mEH gene and also for deletion polymorphisms in the glutathione S-transferase genes, GSTM1 and GSTT1, as potential biomarkers of susceptibility to BD. Our data indicate that the majority of the study subjects (67%) were exposed to very low levels of BD of <150 parts per billion (p.p.b.) time-weighted average (TWA). In some workers, however, we found levels of BD exposures that exceeded a TWA of 2000 p.p.b. Our data indicate a significant (P < 0.05) 2-fold increase in frequencies of hprt variant (mutant) lymphocytes (Vf) in workers exposed to >150 p.p.b. BD, compared with workers exposed to <150 p.p.b. There was no significant effect from individual GSTM1, GSTT1 or mEH genotypes in workers exposed to <150 p.p.b. BD. In workers exposed to >150 p.p.b., individuals with at least one polymorphic mEH His allele (His/His or His/Tyr genotypes) had a significant (P < 0.001) 3-fold increase in Vf (mean Vf x 10(-6) +/- SE = 13.25 +/- 1.78) compared with individuals with the Tyr/Tyr genotype (mean Vf x 10(-6) +/- SE = 4.02 +/- 0.72). There was no significant effect from individual GSTM1 or GSTT1 polymorphisms, but combined polymorphism analysis showed that the genetic damage was highest in individuals who had at least one mEH His allele and either the GSTM1 and/or GSTT1 null genotypes (hprt Vf = 14.19 +/- 2.30 x10(-6)). In contrast, this response was not observed in individuals exposed to levels of BD < 150 p.p.b. These results indicate that polymorphisms in the mEH gene may play a significant role in human sensitivity to the genotoxic effects of BD exposure, and that the hprt mutant lymphocyte assay can serve as a sensitive biomarker of genotoxicity for monitoring occupational exposure to BD in industrial settings. Additional investigations in larger populations of workers are needed to confirm our results and to characterize the possible role of additional mEH polymorphisms in the induction of genetic damage associated with occupational exposure to butadiene.
Carcinogenesis 2001 Mar
PMID:Human sensitivity to 1,3-butadiene: role of microsomal epoxide hydrolase polymorphisms. 1123 81

Breast cancer is the most frequent malignancy among women. Since genetic factors such as BRCA1 and BRCA2 as well as reproductive history constitute only 30% of the cause, environmental exposure may play a significant role in the development of breast cancer. Likewise, the relevant enzymes involved in the biotransformation of xenobiotics (from tobacco smoke, diet or other environmental sources) might play a role in breast carcinogenesis. Since individuals with modified ability to metabolize these carcinogens could have a different risk for breast cancer, we investigated the role of cytochromes P-450 (CYP1A1, CYP2D6), glutathione-S-transferases (GSTM1, GSTT1, GSTP1) and N-acetyltransferases (NAT1, NAT2) gene variants in breast carcinogenesis. A case-control study was conducted on 149 women with breast carcinoma and 207 healthy controls, both of French-Canadian origin. The CYP1A1*4 allele was found to be a significant risk determinant of breast carcinoma (OR = 3.3, 95% CI 1.1-9.7), particularly among post-menopausal women (OR = 4.0, 95% CI 1.2-13.8). The frequency of NAT2 rapid acetylators was increased among smokers (OR = 2.6, 95% CI 0.8-8.2), while the NAT1*10 allele conferred a 4-fold increase in risk among women who consumed well-done meat (OR = 4.4, 95% CI 1.0-18.9). These data suggest that CYP1A1*4, NAT1 and NAT2 variants are involved in the susceptibility to breast carcinoma by modifying the impact of exogenous and/or endogenous exposures.
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PMID:Genetic susceptibility to breast cancer in French-Canadians: role of carcinogen-metabolizing enzymes and gene-environment interactions. 1129 Oct 49

This study was undertaken to determine the effects of occupation, lifestyle and the genetic polymorphisms of cytochrome P450 1A1 (CYP1A1), cytochrome P450 2E1 (CYP2E1) and glutathione S-transferases micro1 (GSTM1) and 1 (GSTT1) on the concentrations of urinary 1-hydroxypyrene (1-OHP) and 2-naphthol among Korean coke oven workers and university students. The study subjects included 90 coke oven workers and 128 university students. A questionnaire was used to obtain detailed data about the work area, smoking habits and food intake of subjects. Associations between urinary polycyclic aromatic hydrocarbon (PAH) concentrations and occupation, smoking status, total airborne PAH level and genetic polymorphisms were tested. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers than in students and correlated significantly with work area. Urinary 2-naphthol concentrations increased with an increase in the level of cigarette smoking in students. Total airborne PAH level correlated with urinary 1-OHP concentration in coke oven workers. Urinary 1-OHP and 2-naphthol concentrations were higher in coke oven workers with the c1/c2 or c2/c2 genotype of CYP2E1 than in those with the c1/c1 genotype. Urinary 2-naphthol concentrations were higher in GSTM1-null workers than in GSTM1-positive workers. In multiple regression analysis CYP2E1 was a significant factor determining urinary 1-OHP concentrations in coke oven workers. CYP2E1 and GSTM1 were significant determinants for urinary 2-naphthol concentrations in coke oven workers and GSTM1 and smoking were prognosticators among university students. Urinary 1-OHP is a better indicator of occupational exposure to PAH in coke oven workers than 2-naphthol, whereas urinary 2-naphthol may be more sensitive for non-occupational inhalation exposure to PAH. In occupationally exposed populations CYP2E1 and GSTM1 appear to play an important role in the metabolism of pyrene and naphthalene. In individuals not occupationally exposed to PAHs GSTM1 and smoking seem to influence the urinary concentration of 2-naphthol.
Carcinogenesis 2001 May
PMID:Effects of occupation, lifestyle and genetic polymorphisms of CYP1A1, CYP2E1, GSTM1 and GSTT1 on urinary 1-hydroxypyrene and 2-naphthol concentrations. 1132 99

The distribution of polymorphisms in the glutathione S-transferase (GST) family genes has been studied in 355 healthy controls and 206 cancer (59 proximal and 147 distal) patients. All controls were subjected to flexible sigmoidoscopy. Odds ratios (OR) after stratification by age, gender and smoking were slightly higher in the cancer group as a whole for GSTM1-null (*0/*0), GSTT1-null (*0/*0) and GSTM3 *A/*B or *B/*B when compared with the control group, but the differences did not reach statistical significance. GSTP1 variants had no effect. Separate analysis of patients with proximal and distal tumours has shown stronger associations for the distal cancers, the GSTM3*B allele presence being significantly more frequent in these patients [OR = 1.77; 95% confidence interval (CI) = 1.15-2.74]. Taking into account strong linkage between the GSTM1*A and GSTM3*B alleles, a separate analysis of the GSTM1-nulled individuals was undertaken. The combination of GSTM1-null genotype with GSTM3*B allele presence (*A/*B or *B/*B) was significantly overrepresented among patients with proximal and distal tumours taken together (OR = 2.12; 95% CI = 1.24-3.63), and especially in distal cancer patients (OR = 2.75; 95% CI = 1.56-4.84). Male individuals displayed a stronger association between the presence of the GSTM1-null in combination with GSTM3 *A/*B or *B/*B and distal tumours with a higher odds ratio (OR = 3.57; 95% CI = 1.73-7.36). In contrast, the frequency of GSTM1 *B/*0 or *B/*B combined with GSTM3 *A/*A was significantly lower in patients with distal colorectal cancer, especially in males (OR = 0.37; 95% CI = 0.15-0.92). Neither of these combinations was associated with proximal tumours. Our findings suggest that interactions of polymorphic genotypes within the GSTM gene cluster affect individual susceptibility to colorectal carcinogenesis, the GSTM3*B variant presence being a risk factor especially in combination with the GSTM1-null genotype.
Carcinogenesis 2001 Jul
PMID:Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor. 1140 49

This study was conducted to investigate the modifying effect of glutathione S-transferase (GST) M1 and T1 polymorphisms on aflatoxin-induced hepatocarcinogenesis among chronic hepatitis B virus surface antigen (HBsAg) carriers. A total of 79 HBsAg-positive cases of hepatocellular carcinoma (HCC) diagnosed between 1991 and 1997 were identified and individually matched to one or two HBsAg-positive controls on age, gender, residence and date of recruitment from the same cancer screening cohort in Taiwan. Blood samples were tested for hepatitis B and C viral markers by enzyme immunoassay and for aflatoxin B(1) (AFB(1))-albumin adducts by competitive enzyme-linked immunosorbent assay. GSTM1 and GSTT1 genotypes were determined by PCR. There was a statistically significant relationship between detectable levels of AFB(1)-albumin adducts in serum and risk of HCC among chronic HBsAg carriers, with an adjusted odds ratio (OR) of 2.0 [95% confidence interval (CI) 1.1-3.7]. In addition, the effect of aflatoxin exposure on HCC risk was more pronounced among chronic HBsAg carriers with the GSTT1 null genotype (OR 3.7, 95% CI 1.5-9.3) than those who were non-null (OR 0.9, 95% CI 0.3-2.4). The interaction between serum AFB(1)-albumin adduct level and GSTT1 genotype was statistically significant (P = 0.03). For GSTM1 the effect of aflatoxin exposure on HCC risk in those with the null genotype was also greater (adjusted OR 2.8, 95% CI 1.0-7.8) than in those with the gene present (adjusted OR 1.8, 95% CI 0.8-4.5), but the difference was not significant (P = 0.91). Notably, when the interaction between aflatoxin exposure and GSTT1 genotype was considered, aflatoxin exposure by itself was not a significant determinant of HCC risk among chronic HBsAg carriers. These results demonstrate the importance of gene-environment interactions in the multifactorial development of HCC.
Carcinogenesis 2001 Aug
PMID:Genetic polymorphisms of glutathione S-transferases M1 and T1 associated with susceptibility to aflatoxin-related hepatocarcinogenesis among chronic hepatitis B carriers: a nested case-control study in Taiwan. 1147 Jul 60

Glutathione S-transferases (GSTs) are metabolic phase II enzymes that promote reactive metabolite elimination by conjugating them to glutathione (GSH). Because of their important role in xenobiotic metabolism and detoxification, they have been implicated in carcinogenesis processes, especially epithelium transformation. Moreover, their influence on response to chemotherapy in cancer patients has been demonstrated. Genetic polymorphisms for GSTM1, GSTT1 and GSTP1 have been found in human populations and have been shown to have phenotypic consequences. To investigate the role of GST enzymes in carcinogenesis and in response to chemotherapy in patients with head and neck squamous cell carcinoma (HNSCC), GSTP1, GSTM1 and GSTT1 were studied prospectively in a large series of HNSCC patients. Correlations between GST alterations, p53 mutation status and clinical response to chemotherapy were investigated. We showed that the risk of developing laryngeal cancer was increased by 2.6-fold [95% CI 1.6--6.1] in patients with the GSTM1 null genotype and by 2.8-fold [95% CI 0.9--8.1] in patients with the homozygous GSTP1 val105 genotype. Furthermore, individuals with this latter genotype were over-represented in the p53 mutation group (p = 0.05). After storage duration and hemolysis adjustment, a significantly lower plasmatic GSTP1 level was observed in complete responders compared with partial and non-responders (mean: 4.4 +/- 0.06 microg/l, 4.7 +/- 0.06 microg/l and 4.7 +/- 0.07 microg/l; p = 0.05), respectively. The prevalence of p53-mutated tumors was significantly higher in the group of non-responders (81%) compared with partial (60%) and complete responders (64%) (p = 0.05). Two types of multivariate analysis were performed including parameters that have been shown to influence response to chemotherapy significantly in univariate analysis. p53 mutations and high tumor stage are independent factors of non-response to chemotherapy, whereas plasmatic GSTP1 levels and low tumor stage are independent factors of complete response. Our data suggest that GST enzymes are associated with larynx cancer and that their use as predictive factors and treatment targets should be further explored.
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PMID:Glutathione-associated enzymes in head and neck squamous cell carcinoma and response to cisplatin-based neoadjuvant chemotherapy. 1147 86

Glutathione S-transferases (GSTs) detoxify potentially mutagenic and toxic DNA-reactive electrophiles, including metabolites of several chemotherapeutic agents, some of which are suspected human carcinogens. Functional polymorphisms exist in at least three genes that encode GSTs, including GSTM1, GSTT1, and GSTP1. We hypothesize, therefore, that polymorphisms in genes that encode GSTs alter susceptibility to chemotherapy-induced carcinogenesis, specifically to therapy-related acute myeloid leukemia (t-AML), a devastating complication of long-term cancer survival. Elucidation of genetic determinants may help to identify individuals at increased risk of developing t-AML. To this end, we have examined 89 cases of t-AML, 420 cases of de novo AML, and 1,022 controls for polymorphisms in GSTM1, GSTT1, and GSTP1. Gene deletion of GSTM1 or GSTT1 was not specifically associated with susceptibility to t-AML. Individuals with at least one GSTP1 codon 105 Val allele were significantly over-represented in t-AML cases compared with de novo AML cases [odds ratio (OR), 1.81; 95% confidence interval (CI), 1.11-2.94]. Moreover, relative to de novo AML, the GSTP1 codon 105 Val allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR, 2.66; 95% CI, 1.39-5.09), particularly among those with prior exposure to known GSTP1 substrates (OR, 4.34; 95% CI, 1.43-13.20), and not among those t-AML patients with prior exposure to radiotherapy alone (OR,1.01; 95% CI, 0.50-2.07). These data suggest that inheritance of at least one Val allele at GSTP1 codon 105 confers a significantly increased risk of developing t-AML after cytotoxic chemotherapy, but not after radiotherapy.
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PMID:Polymorphism in glutathione S-transferase P1 is associated with susceptibility to chemotherapy-induced leukemia. 1155 69

Oral cancer ranks first among all cancers in males and is the third most common among females in India. Tobacco-derived carcinogens are involved in the development of oral cancer. Environment-gene interaction in oral carcinogenesis is well demonstrated by phase I and II enzymes that are involved in the metabolism of carcinogens. This study looked at the significance of genetic polymorphisms in CYP1A1, GSTM1 and GSTT1 genes in patients with oral cancer. The study included 98 oral cancer patients and 60 age and sex matched healthy controls. Genotypes of CYP1A1, GSTM1 and GSTT1 were determined by PCR-RFLP. GSTM1 null deletion was observed in 49% of oral cancer cases and 33% of control subjects. For GSTT1, 18% of carcinomas and 8% of controls had the null genotype. In the case of CYP1A1 m2 allele, 51% of oral cancers and 17% of normal controls, respectively, had one or both alleles with the isoleucine-->valine substitution. Digestion of the PCR products with enzyme Nco1 revealed polymorphism for CYP1A1 m2 with bands at 263 bp. There was no association between genotypes with tumor size, stage, grade, and age. Since null genotype individuals may possibly be poor detoxifiers with reduced ability to neutralise the reactive carcinogenic intermediates, they may be a high risk category. The frequency distribution of CYP1A1 m2 (Ile/val) genotypes among oral cancer patients was significantly different that from normal controls. The risk of CYP1A1 can be supported by the functional difference between presence of valine and isoleucine; valine type has higher catalytic and mutagenic activity towards benzo[a] pyrene than the isoleucine type. In conclusion, our results suggest that polymorphism in CYP1A1 m2 gene and/or GSTM1 and GSTT1 null genotype may confer an increased risk for oral cancer.
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PMID:Genetic polymorphism of CYP1A1, GSTM1 and GSTT1 genes in Indian oral cancer. 1156 81

The glutathione S-transferase (GST) genes are involved in the metabolism of various carcinogens. Deletion polymorphisms in the GSTM1 and GSTT1 genes and an A-G polymorphism in the GSTP1 gene were investigated in relation to breast cancer risk in 500 breast cancer patients and 395 controls. The effects of the GST genotypes on the frequency and pattern of p53 mutations in 388 breast carcinomas were also studied. A suggestive trend of increasing risk of breast cancer with increasing number of G alleles of the GSTP1 was observed (P for trend, 0.11). The GSTM1 and GSTT1 polymorphisms did not show an association with breast cancer. No increase in risk was observed with a combination of genotypes. A statistically significant association was observed between the GSTT1 genotype and p53 mutation status of the tumors, with patients carrying the GSTT1 null genotype more frequently having mutations in the p53 gene compared with patients with a GSTT1 gene present (24.6% versus 12.4%; P = 0.019). There was also a suggestive trend for the GG genotype of the GSTP1 gene, but it was not statistically significant (P = 0.19). No association was observed with the type or location of mutations. We conclude that the GSTP1 and GSTT1 genes could play a role in carcinogenesis in the breast, possibly through increased frequency of mutations in tumor suppressor genes such as p53.
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PMID:GSTM1, GSTT1, and GSTP1 genotypes in relation to breast cancer risk and frequency of mutations in the p53 gene. 1170 Feb 65

Mounting epidemiological evidence suggests that smoking may play a role in the etiology of breast cancer. Because smoking-related DNA adducts are detectable in both normal and malignant breast tissues, we hypothesized that breast cancer patients may be sensitive to tobacco-induced carcinogenesis, and this sensitivity could be modulated by variants of metabolic genes. To test this hypothesis, we evaluated benzo(a)pyrene diol-epoxide (BPDE)-induced mutagen sensitivity and polymorphisms of GSTM1 and GSTT1 in a pilot case-control study of breast cancer. Short-term cell cultures were established from blood samples of 100 female breast cancer patients and 105 healthy controls. After 5 h of in vitro exposure to 4 microM of BPDE, we harvested the lymphocytes for cytogenetic evaluation and recorded and compared the frequency of BPDE-induced chromatid breaks between cases and controls. We used a multiplex PCR-based assay to simultaneously detect polymorphisms of GSTM1 and GSTT1 from genomic DNA. We performed univariate and multivariate logistic regression analyses and calculated odds ratios (OR) and 95% confidence intervals (CIs). Cases had a significantly higher frequency of chromatid breaks than did controls (P < 0.0001). The level of chromatid breaks greater than the median value of controls was associated with a >3-fold increased risk of breast cancer [adjusted odds ratio (ORadj) = 3.11; 95% CI = 1.72-5.64]. The risk was more pronounced in those who were < 45 years (ORadj = 4.79; 95% CI = 1.87-12.3), ever-smokers (ORadj = 5.55; 95% CI = 1.85-16.6), alcohol drinkers (ORadj = 4.64; 95% CI = 1.70-12.7), and those who had the GSTT1 null variant (ORadj = 8.01; 95% CI = 1.16-55.3). These data suggest that sensitivity to BPDE-induced chromosomal aberrations may contribute to the risk of developing breast cancer, and such sensitivity may be modulated by both genetic and environmental factors. Larger studies are needed to confirm our findings.
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PMID:Sensitivity to benzo(a)pyrene diol-epoxide associated with risk of breast cancer in young women and modulation by glutathione S-transferase polymorphisms: a case-control study. 1173 29


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