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

An individual difference in the susceptibility to chemical carcinogens is one of the most important factors in the estimate of risk of human cancer. Recently, it has been reported that genetic risk for tobacco-related cancers is associated with polymorphisms of the CYP1A1 and GSTM1 genes in terms of genotype frequencies and cigarette smoking dose. In this study, we investigated the inter-individual difference in genetically determined susceptibility to oral squamous cell carcinoma (SCC) in relation to cigarette smoking dose in a Japanese population. DNA samples were obtained from both patients and controls. We identified individuals at high risk genetically for oral SCC in terms of polymorphisms of the CYP1A1 and GSTM1 genes. This study then compared the estimated total number of cigarettes smoked by patients with those smoked by controls. In this case-control study, we estimated the odds ratios of susceptible to non-susceptible individuals. CYP1A1 genotype C and GSTM1 deficiency were frequently found among oral SCC patients. Patients with genotype C and GSTM1 deficiency contracted carcinoma after fewer cigarettes than those with other genotypes. Individuals with these two genotypes were at remarkably high risk at a low dose level of cigarette smoking. Individual differences in polymorphisms of the CYP1A1 and GSTM1 genes is one important factor in the estimate of risk of oral SCC at a low dose level of cigarette smoking.
Carcinogenesis 1999 Oct
PMID:Genetic polymorphism of drug-metabolizing enzymes and susceptibility to oral cancer. 1050 6

Epidemiological studies suggest that aflatoxin B(1) (AFB(1)), a mycotoxin produced by certain Aspergillus species, may play a role in human respiratory cancers in occupationally-exposed individuals. AFB(1) requires bioactivation to the corresponding exo-8,9-epoxide for carcinogenicity, and glutathione S-transferase (GST)-catalyzed conjugation of the epoxide with glutathione (GSH) is a critical determinant of susceptibility to AFB(1). Of the purified human GST enzymes studied, the polymorphic hGSTM1-1 has the highest activity towards AFB(1) exo-epoxide. The influence of the GSTM1 polymorphism on AFB(1)-GSH formation, as well as the abilities of cytosols from preparations enriched in different isolated lung cell types to conjugate AFB(1)-epoxides, were examined. In whole-lung cytosols from patients undergoing clinically indicated lobectomy, GSTM1 genotype correlated with GSTM1 phenotype as determined by [(3)H]trans-stilbene oxide conjugation: GSTM1-positive = 295 +/- 31 pmol/mg/h (n = 6); GSTM1-negative = 92.8 +/- 23.3 pmol/mg/h (n = 4) (P < 0.05). In contrast, conjugation of microsome-generated [(3)H]AFB(1)-epoxides with GSH was low and variable between patients, and did not correlate with GSTM1 genotype: GSTM1-positive = 11.9 +/- 8.1, 111 +/- 66 and 510 +/- 248 fmol/mg/h (n = 6); GSTM1-negative = 15.3 +/- 16.7, 167 +/- 225 and 540 +/- 618 fmol/mg/h (n = 4) (for 1, 10 and 100 microM [(3)H]AFB(1), respectively). GSH conjugates of AFB(1) exo-epoxide and the much less mutagenic stereoisomer AFB(1) endo-epoxide were produced in a ratio of approximately 1:1 in cytosols from both whole lung and isolated cells. Total cytosolic AFB(1)-epoxide conjugation was significantly higher in fractions enriched in alveolar type II cells (3.07 +/- 1.61 pmol/mg/h) than in unseparated lung cells (0.143 +/- 0.055 pmol/mg/h) or fractions enriched in alveolar macrophages (0. 904 +/- 0.319 pmol/mg/h; n = 4) (P < 0.05). Furthermore, AFB(1)-GSH formation and percentage of alveolar type II cells in different cell fractions were correlated (r = 0.78, P < 0.05). These results demonstrate that human lung GSTs exhibit very low conjugation activity for both AFB(1)-8,9-epoxide stereoisomers, and that this activity is heterogeneously distributed among cell types, with alveolar type II cells exhibiting relatively high activity. Of the GSTs present in human peripheral lung which contribute to AFB(1) exo- and endo-epoxide detoxification, hGSTM1-1 appears to play at most only a minor role.
Carcinogenesis 1999 Oct
PMID:Glutathione S-transferase-catalyzed conjugation of bioactivated aflatoxin B(1) in human lung: differential cellular distribution and lack of significance of the GSTM1 genetic polymorphism. 1050 13

The modulation of benzo[a]pyrene diolepoxide (BPDE)-DNA adduct levels by polymorphisms in the CYP1A1, GSTM1 and GSTT1 genes was assessed in leukocytes of Caucasian males. Eighty-nine coke oven workers (35 smokers, 36 ex-smokers and 18 non-smokers) were recruited from job categories with different exposure levels to polycyclic aromatic hydrocarbons (PAH), together with 44 power plant workers (all smokers) not exposed to PAH. BPDE-DNA adducts were detected in 69 of 133 (52%) DNA samples with a 100-fold variation (range 0.2-44 adducts/10(8) nt) and a median of 1.6 adducts/10(8) nt. All samples with the GSTM1 active genotype (n = 59) and five out of 74 samples with GSTM1*0/*0 (7%) showed non-detectable adducts (<0.2 adducts/10(8) nt) and 69 of 74 subjects with GSTM1*0/*0 (93%) had detectable adducts (>0.2 adducts/10(8) nt). The difference in adduct level between the GSTM1*0/*0 and GSTM1 active genotypes was highly significant (P < 0.0001). No significant difference in adduct level between the GSTT1*0/*0 and GSTT1 active genotypes was seen. All heterozygotes (CYP1A1*1/*2) from subjects of GSTM1 active type did not have detectable adducts. Among the GSTM1-deficient individuals (n = 69), 42 with the CYP1A1*1/*1 genotype showed a lower adduct level (median 1.3, range 0.2-4.1 adducts/10(8) nt) compared with 26 individuals with heterozygous mutated CYP1A1*1/*2 genotypes (median 2.5, range 0.4-6.1 adducts/10(8) nt, P < 0.015). One individual with low PAH exposure and the rare combination CYP1A1*2A/*2A-GSTM1*0/*0 showed an extremely high level of 44 adducts/10(8) nt. Significant differences in detectable adduct levels were found between the CYP1A1*1/*1 and CYP1A1*1/*2 genotypes in the exposed group low + medium (P = 0.01) and for all adduct levels, detectable and non-detectable (set at a fixed value), in highly exposed individuals and in ex-smokers (P = 0.03), whereas no such differences were observed in the control group. Mutated CYP1A1*1/*2 increased the adduct level in non-smokers from the exposed group (1.4 versus 2.2 adducts/10(8) nt), but had no effect on the smokers from the exposed group (2.3 versus 2.8 adducts/10(8) nt). When all variables were dichotomized, statistical evaluation showed that CYP1A1 status (P = 0.015), PAH exposure (P = 0.003) and smoking (P = 0.006) had significant effects on adduct levels which increased in the order: CYP1A1*1/*1 < CYP1A1(*1/*2 or *2A/*2A); environmental exposure < occupational exposure; non-smokers < smokers, whereby adducts increased with cigarette dose and the duration of smoking. Higher levels of BPDE-DNA adducts in individuals with the combined CYP1A1(1/*2 or *2A/*2A)-GSTM1*0/*0 genotype suggest that these genotype combinations are at increased risk for contracting lung cancer when exposed to PAH.
Carcinogenesis 2000 Jan
PMID:Modulation of benzo[a]pyrene diolepoxide-DNA adduct levels in human white blood cells by CYP1A1, GSTM1 and GSTT1 polymorphism. 1060 31

While 1,3-butadiene is carcinogenic in rodents, cancer causation in humans is less certain. We examined a spectrum of genotoxic outcomes in 41 butadiene polymer production workers and 38 non-exposed controls, in China, to explore the role of butadiene in human carcinogenesis. Because in vitro studies suggest that genetic polymorphisms in glutathione S-transferase enzymes influence genotoxic effects of butadiene, we also related genotoxicity to genetic polymorphisms in GSTT1 and GSTM1. Among butadiene-exposed workers, median air exposure was 2 p.p.m. (6 h time-weighted average), due largely to intermittent high level exposures. Compared with unexposed subjects, butadiene-exposed workers had greater levels of hemoglobin N-(2,3,4-trihydroxybutyl)valine (THBVal) adducts (P < 0.0001) and adduct levels tended to correlate, among butadiene-exposed workers, with air measures (P = 0.03). Butadiene-exposed workers did not differ, however, from unexposed workers with respect to frequency of uninduced or diepoxybutane-induced sister chromatid exchanges, aneuploidy as measured by fluorescence in situ hybridization of chromosomes 1, 7, 8 and 12, glycophorin A variants or lymphocyte hprt somatic mutation. Also among the exposed, greater THBVal levels were not associated with increases in uninduced sister chromatid exchanges, aneuploidy, glycophorin A or hprt mutations. Butadiene-exposed workers had greater lymphocyte (P = 0.002) and platelet counts (P = 0.07) and lymphocytes as a percentage of white blood cells were moderately correlated with greater THBVal levels (Spearman's phi = 0.32, P = 0.07). Among butadiene-exposed workers, neither GSTM1 nor GSTT1 genotype status predicted urinary mercapturic acid butanediol formation, THBVal adducts, uninduced sister chromatid exchanges, aneuploidy or mutations in the glycophorin A or hprt genes. Overall, the study demonstrated exposure to butadiene in these workers, by a variety of short-term and long-term measures, but did not show specific genotoxic effects, at the chromosomal or gene levels, related to that exposure.
Carcinogenesis 2000 Jan
PMID:Genotoxic markers among butadiene polymer workers in China. 1060 34

The 'Mediterranean diet', a diet rich in cereals, fruit and vegetables, has been associated with lowering the risk of a variety of cancers of the digestive tract and the bladder. In a previous study, we showed that the high phenolic content these dietary components produce in the urine could be associated with higher antimutagenic properties of the urine and lower arylamine-DNA adducts in exfoliated bladder cells. We have conducted a case-control study on 162 bladder cancer patients and 104 hospital controls. Total aromatic DNA adducts were measured in white blood cells (WBC) of all subjects by (32)P-post-labelling. Genetically based metabolic polymorphisms were analysed by PCR-RFLP (NAT2, GSTM1, GSTT1, GSTP1, COMT and NQO1). All subjects were interviewed about their tobacco use, dietary habits and other risk factors. The odds ratio (OR) for the risk of bladder cancer according to the presence/absence of WBC DNA adducts (detection limit 0.1 RALx10(8)) was 3.7 [95% confidence interval (CI) 2.2-6.3] and a dose-response relationship with levels of adducts was apparent. The association between case/control status and the presence of WBC DNA adducts was significantly stronger in the subjects who consumed fewer portions of fruit or vegetables per day (OR 7.80, 95% CI 3.0-20.30 for 0-1 portions of vegetables) than in the heavy consumers (OR 4.98 for consumers of 2 portions daily, OR 1.97 for consumers of > or =3 portions; similar but lower estimates were found for the intake of fruit). No association was noticed between tobacco smoking and WBC DNA adducts. Only NAT-2, among the several genotypes considered, was associated in a statistically significant way with the risk of bladder cancer (OR 1.72, 95% CI 1.03-2.87) and with the levels of WBC DNA adducts. Our report suggests that fruit and vegetables could protect against bladder cancer by inhibiting the formation of DNA adducts.
Carcinogenesis 2000 Feb
PMID:White blood cell DNA adducts and fruit and vegetable consumption in bladder cancer. 1065 56

Chemopreventives are chemicals that prevent the formation of cancers such as oral cancer. They can take the form of nutrients or synthetic molecules, and their fundamental characteristic is that they do not produce disease processes that would result in debilitating symptoms. Current evidence indicates that they function by modifying the oxidative state of transforming cells. Biomarkers can take the form of genetic and molecular indicators, which characterize the function of chemopreventives and cancer processes such as oral carcinogenesis. Biomarkers cannot provide all the required information for risk assessment or possible activity of the chemopreventives. Other methods, such as epidemiological analyses and techniques, must be used to enhance our understanding of the risk for oral cancer in human populations. One common epidemiologic method, the questionnaire, helps to determine the use and carcinogenic potential of tobacco and alcohol during oral carcinogenesis. Genetic and molecular changes in human patient populations may result in a reduction in the number and function of tumor suppressor genes. If these changes are to be assessed, the tissues (e.g., buccal mucosa) must be accessible and harvested in a reliable and consistent manner for the acquisition of DNA, mRNA, and protein. Oral tissues provide sufficient quantities of these molecules and, under stringent conditions, the quality required for the isolation of these molecular constituents. In conjunction with epidemiologic techniques, various genotypic polymorphisms, such as glutathione-S-transferase (GSTM1) or cytochrome P450 (CYP450A1), have indicated a loss in carcinogen detoxification or the processing of internal growth control signals. Biomarkers are composed of a large diverse group of genetic and molecular structures. Some of these biomarkers are indicators for programmed cell death (PCD), while others describe malignant tumor growth. Many of these classes of molecules are oxidative-responsive (e.g., tumor suppressor p53, Bcl-2, growth factors, immune-derived proteins, and death-inducing molecules) and induce PCD by triggering a cascade of cysteine proteases and regulators (e.g., caspases, death receptors). This pathway results in cell-cycle alterations and DNA fragmentation. It is hoped that a detailed knowledge of the processes involved in malignant transformation will better define the biomarker-screening tools for oral cancer. These tools will enhance our ability to predict the incidence of cancer, detect early malignant change, and quantitate chemoprevention during oral carcinogenesis. Chemopreventives such as the retinoids have already demonstrated their ability to suppress potential malignant changes in pre-malignant oral leukoplakias and decrease the incidence of second head-and-neck cancer primaries. It is our hope that this review will increase investigators' interest in developing new screening and detection systems for oral cancer.
 ...
PMID:Biomarkers and molecular epidemiology and chemoprevention of oral carcinogenesis. 1068 2

Certain human biotransformation enzymes have been implicated in the formation and scavenging of the ultimate reactive metabolites, the diolepoxides, from polycyclic aromatic hydrocarbons (PAHs). In the present study, performed on aluminum smelter workers, we have analyzed airborne PAH, the pyrene metabolite 1-hydroxypyrene (1-OHP) in urine, and genotypes for biotransformation enzymes involved in PAH metabolism. The aim was to evaluate the correlation between external exposure and biomarkers of exposure and to investigate to what extent genetic polymorphism in metabolic enzymes can explain interindividual variation in urinary 1-OHP levels. DNA was prepared from blood samples from 98 potroom workers and 55 controls and altogether eight polymorphisms in the CYP1A1, mEH, GSTM1, GSTP1 and GSTT1 genes were analyzed. The 1-OHP excretion was found to correlate significantly (P </= 0.005) to the exposure. The interindividual difference in excretion of 1-OHP was vast (>100-fold) and univariate and multivariate regression analyses were used to find the variables that could determine differences in excretion. The variation could, to some degree, be explained by differences in exposure to airborne particulate-associated PAHs, the use of personal respiratory protection devices, smoking habits and genetic polymorphisms in the cytochrome P450 1A1, GSTM1 and GSTT1 enzymes. The part of the variance that could be explained by differences in biotransformation genotypes seemed to be of the same order of magnitude as the variance explained by differences in exposure. In the control group as well as in the occupationally exposed group, the highest 1-OHP levels were observed in individuals carrying the CYP1A1 Ile/Val genotype who were also of the GSTM1 null genotype. The results show that urinary 1-OHP is a sensitive indicator of recent human exposure to PAHs and that it may also to some extent reflect the interindividual variation in susceptibility to PAHs.
Carcinogenesis 2000 Apr
PMID:CYP1A1 and GSTM1 polymorphisms affect urinary 1-hydroxypyrene levels after PAH exposure. 1075 2

An association of oral squamous cell carcinoma (SCC) susceptibility with an MspI restriction site polymorphism of the CYP1A1 gene and GSTM1 polymorphism were reported in our previous study (Sato M, Sato T, Izumo T, Amagasa T. Genetic polymorphism of drug-metabolizing enzymes and susceptiblility to oral cancer. Carcinogenesis 1999;20:1927-31). We report here that genetic risk for oral SCC was associated with another isoleucine-valine (Ile-Val) polymorphism, which resulted in an Ile-Val amino acid replacement in the heme-binding region of CYP1A1, and combined genotyping of CYP1A1 and GSTM1 genes in relation to the cumulative cigarette-smoking dose. The genetic polymorphisms of CYP1A1 and GSTM1 genes in oral cancer susceptibility were assessed by examining polymorphic prevalences in 142 oral SCC patients and 142 healthy controls who were individually matched to the patients with respect to sex and age (+/-1 year). Individuals with a combined genotype of Val/Val and GSTM1(-) were at an increased risk for oral SCC compared with other combined genotypes, in particular, at a low dose level of cigarette smoking.
 ...
PMID:Genetically high susceptibility to oral squamous cell carcinoma in terms of combined genotyping of CYP1A1 and GSTM1 genes. 1079 29

Induction or inhibition of biotransformation enzymes, enzymes that activate or detoxify numerous xenobiotics, is one mechanism by which vegetables may alter cancer risk. Using a randomized crossover design, we examined the effect of various vegetable diets on cytochrome P450 (CYP) 1A2, N-acetyltransferase 2 (NAT2) and xanthine oxidase activity in humans. Men and women, non-smokers, on no medication and 20-40 years of age ate four 6-day controlled diets: basal (vegetable-free) and basal with three botanically defined vegetable groups. Enzyme activities were determined by measuring urinary caffeine metabolite ratios after a 200 mg caffeine dose on the last day of each feeding period. Mean CYP1A2 activity for 19 men and 17 women (least squares means adjusted for sex, GSTM1 genotype, urine volume and feeding period) with basal, brassica, allium and apiaceous vegetable diets differed significantly (P </=ISOdia</= 0. 0005) by diet, irrespective of the caffeine metabolite molar ratio used to describe CYP1A2 activity; brassica vegetables increased (P <0.04) and apiaceous vegetables decreased (P </=ISOdia</= 0.02) activity compared with the basal and allium diets. There was no effect of diet on NAT2 and xanthine oxidase activities and none of the subjects differed by GSTM1 genotype. These results demonstrate that while one vegetable subgroup induces human CYP1A2 activity, another subgroup inhibits it. This points to a complex association between consumption of a typical diet of various vegetables and biotransformation enzyme activities in humans, an association that may be difficult to interpret in observational studies.
Carcinogenesis 2000 Jun
PMID:Brassica vegetables increase and apiaceous vegetables decrease cytochrome P450 1A2 activity in humans: changes in caffeine metabolite ratios in response to controlled vegetable diets. 1083 4

A valine-108-methionine polymorphism in exon 4 of the catechol-O-methyltransferase (COMT) gene causes a 3- to 4-fold reduction in enzyme activity and has been associated with an increased risk of breast cancer. This increased risk may be attributable to a decreased ability of the protein encoded by the low-activity allele (COMT(L)) to methylate and inactivate catechol estrogens, which have been implicated in estrogen carcinogenesis. Because estrogens have also been implicated in the etiology of ovarian cancer, we analyzed 108 cases and 106 controls from a case-control study conducted in Mainz, Germany, to test the hypothesis that COMT(L) is associated with ovarian cancer risk. No significant association was found between the COMT genotype and ovarian cancer risk (for the intermediate-activity COMT genotype versus the high-activity COMT genotype, OR, 1.29; 95% CI, 0.63-2.64; for the low-activity COMT genotype versus the high-activity COMT genotype, OR, 1.17; 95% CI, 0.52-2.61). We also hypothesized that women who were both low-activity COMT genotype- and glutathione S-transferase (GST) M1- and/or T1 null would be at higher risk for ovarian cancer because the combination of these genotypes could theoretically lead to higher catechol estrogen exposure. However, the association between the COMT polymorphism and ovarian cancer risk was similar across GSTM1 and GSTT1 genotypes (Ptrend > 0.40, for all strata). Because of the small sample size of this study population, odds ratios of a small magnitude could not be completely ruled out; however, the results presented do not support a strong association between the COMT polymorphism and the risk of ovarian cancer.
 ...
PMID:Catechol-O-methyltransferase polymorphism is not associated with ovarian cancer risk. 1114 24


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>