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)

We have studied the mutant frequency in the human gene for hypoxanthine-guanine phosphoribosyl transferase (hprt) using the T-cell cloning assay, the aromatic DNA adduct level using the 32P-postlabelling assay, and related the levels of these biomarkers to the genotypes for glutathione transferase (GST mu) and N-acetyltransferase (NAT2) in non-smoking bus maintenance workers exposed to diesel exhaust. No difference in mutant frequency was observed between the 47 exposed (8.6 x 10(-6), age range 27-65) and the 22 control individuals (8.4 x 10(-6), age range 23-61), while the difference in adduct level (3.2 versus 2.3 x 10(-8)) was highly significant (P = 0.0009). Both mutant frequency and adduct level were highest in the 16 most heavily exposed workers. Overall, a significant increase of mutant frequency was observed with adduct level (P = 0.008) as well as with age (P < 0.0001). The age dependence was higher in the GSTM1-negative slow acetylators (3.1%/year) as compared to the three other genotype combinations (2.4-2.5%/year). There was no significant difference in mutant frequency or in adduct level between the GSTM1-negative (49.3% of the population) and positive individuals, or between the slow (60.9% of the population) and rapid acetylators. Among the slow acetylators, however, a significantly higher adduct level (P = 0.03) was obtained for the GSTM1-negative individuals as compared to the GSTM1-positive individuals. These results suggest a possible role of both GST mu and NAT2 for individual susceptibility to carcinogen exposure.
Carcinogenesis 1995 Aug
PMID:Relationship between hprt mutant frequency, aromatic DNA adducts and genotypes for GSTM1 and NAT2 in bus maintenance workers. 754 77

Genes for cytochrome P4501A1 (CYP1A1) and glutathione S-transferase class mu (GSTM1) have been shown to be polymorphic, and have been implicated in tobacco-related carcinogenesis. In the present study, the role of the combined genotypes CYP1A1 and GSTM1 as a possible modulator of smoking related lung cancers was studied in relation to the tobacco smoke exposure level in 118 Japanese patients aged < 70 with squamous or small cell carcinomas of the lung. Among male smoking patients, the overall proportion of the GSTM1 null genotype (GSTM1[-]) was slightly higher than among healthy male smoker controls (56.7% versus 48.1%, P = 0.17). Little difference was observed between smoker patients and corresponding controls in overall frequencies of m2 mutant allele homozygotes (CYP1A1[m2/m2]) (16-18%) and Val encoding allele homozygotes (5-6%). However, when subjects were categorized by both CYP1A1 genotype (MspI polymorphism) and GSTM1 genotype, GSTM1(-) became markedly more expressed in patients with CYP1A1(m2/m2) when compared to the corresponding smoker controls (81.3% versus 39.4%, P < 0.01). When odds ratios were estimated using nonsmoking patients and healthy controls as a reference, the relative risk for developing lung cancer was found to increase in a cigarette dose-dependent manner across all combinations of genotypes. Furthermore, a 7- to 8-fold variation in risk was found among the various combinations; 3.2 in individuals with combined GSTM1(+) and CYP1A1(m2/m2) and 21.9 in those with combined GSTM1(-) and CYP1A1(m2/m2) genotype when the smoking index (sigma cigarettes smoked per day x years of smoking) was set at > or = 800. The results suggest that individuals having CYP1A1(m2/m2) are relatively resistant to tobacco-related lung cancers when combined with GSTM1(+), but are highly susceptible when combined with GSTM1(-). Combined CYP1A1 and GSTM1 genotype is thus a potential predictor of genetic susceptibility to smoking-related lung cancers in populations where CYP1A1 m2 or Val alleles are common.
Carcinogenesis 1995 Oct
PMID:Risk of smoking for squamous and small cell carcinomas of the lung modulated by combinations of CYP1A1 and GSTM1 gene polymorphisms in a Japanese population. 758 31

We describe studies to determine if susceptibility to pituitary tumours is associated with the putatively high risk GSTM1 null and CYP2D6 EM genotypes. Frequency distributions of these genotypes were similar in cases and controls though the frequency of CYP2D6 PM and GSTM1 B tended to be lower (P = 0.072 and P = 0.095 respectively) in the tumour group. Immunopositivity for p53 was found in 18/97 tumours. In these samples GSTM1 null (39%) and CYP2D6 EM (56%) frequencies were not different to those in controls. The frequencies of CYP2D6 PM and GSTM1 B in the p53 immunonegative tumours tended to be lower (P = 0.055 and P = 0.1185 respectively) than in controls. Mutations in gsp and ras were studied using the polymerase chain reaction and allele specific oligonucleotide analysis. Eight of 19 somatotrophinomas demonstrated mutations in gsp; frequencies of GSTM1 null and CYP02D6 EM were similar to controls. No ras mutations were identified in 55-tumour studies. The data indicate the GSTM1 null and CYP2D6 EM genotypes are not associated with altered expression of p53 or, mutation of gsp and ras in these adenomas and, suggest the CYP2D6 PM genotype is associated with a reduced risk of pituitary adenomas and, that GSTM1*B confers greater protection than GSTM1*A.
Carcinogenesis 1995 Jul
PMID:GSTM1 and CYP2D6 genotype frequencies in patients with pituitary tumours: effects on P53, ras and gsp. 761

The M1 member of the Mu subclass of glutathione S-transferase (GSTM1) is only expressed in about 50% of individuals. In contrast, GSTT1, a member of the theta class which has been recently shown to be polymorphic, is expressed in 85% of Australian individuals. Previous studies have shown a significant excess of homozygous null GSTM1 genotypes among individuals with colorectal cancer, particularly those with proximal tumours. This suggests that GSTM1 plays a role in susceptibility to this neoplasm. In this study of 132 individuals with colorectal cancer and 200 controls, no significant excess of GSTM1 homozygous null genotypes was found among colorectal cancer patients with either a proximal or distal tumour. This suggests that the association between GSTM1 homozygous null genotypes and colorectal cancer is of smaller effect than has been reported previously using larger sample sizes. We have also examined the frequency of homozygous null GSTT1 genotypes in patients with colorectal cancer. Although the frequency was not significantly different in cases compared to control individuals, GSTT1 null homozygotes were significantly more common in patients who were diagnosed before the age of 70 years than in those who were diagnosed at an older age. This suggests that the GSTT1 genotype, and perhaps also the GSTM1 genotype for which a similar, but non-significant effect was seen, might influence the age of onset of colorectal cancer.
Carcinogenesis 1995 Jul
PMID:Glutathione S-transferase M1 and T1 polymorphisms: susceptibility to colon cancer and age of onset. 761 2

The GSTM1 gene on chromosome 1p encodes the carcinogen-detoxification enzyme, glutathione S-transferase (mu subclass). The homozygous null genotype at this locus has been associated with increased susceptibility to malignancy, including some skin cancers. One hundred and twenty-four Australian patients with sporadic melanoma and 62 with familial basal cell carcinomas (a feature of nevoid basal cell carcinoma syndrome, NBCCS) were examined for germline homozygous deletions of GSTM1 using multiplex polymerase chain reactions. The homozygous null genotype was not overrepresented in either those with a single melanoma or in the NBCCS cases. Nor did it significantly accelerate tumorigenesis in either group. Analyses of much larger sample sizes will be required to investigate the representation of the null genotype in patients with multiple melanoma primaries and in those with melanoma co-existing with other non-cutaneous malignancies.
Carcinogenesis 1995 Aug
PMID:Glutathione S-transferase GSTM1 null genotype is not overrepresented in Australian patients with nevoid basal cell carcinoma syndrome or sporadic melanoma. 763 33

Japanese urothelial (bladder, renal pelvis and ureter) cancer patients (n = 83) and community controls (n = 101) were compared for rates of polymorphism in exon 7 of the cytochrome P4501A1 (CYP1A1) gene or homozygous deletion of the glutathione S-transferase class mu (GSTM1) gene. A CYP1A1 polymorphism was detected in a HinCII polymorphism assay utilizing a primer with a single base pair mismatch. The frequency distribution of the CYP1A1 genotypes in urothelial cancer patients showed no significant difference from that in healthy controls. The increased frequency of homozygous deletions of GSTM1 gene loci in patients with urothelial cancer was statistically significant compared with the controls, 51 of 83 (61%) and 43 of 101 (43%) (odds ratio = .2.15, 95% confidence interval = 1.18-3.86). These results lead us to conclude that homozygous deletion of the GSTM1 gene may be associated with susceptibility to urothelial cancer.
Carcinogenesis 1995 Mar
PMID:Cytochrome P4501A1 gene polymorphism and homozygous deletion of the glutathione S-transferase M1 gene in urothelial cancer patients. 769 28

The relationships between smoking and the expression of glutathione S-transferase (GST*) isozymes GSTM1-1, GSTM3-3, GSTP1-1 and GSTA1-1/2-2 (GSTA1/2), or between smoking and activities of epoxide hydrolase (EH) and aryl hydrocarbon hydroxylase (AHH) were investigated in lung samples from 27 patients with lung cancer and 11 control patients by immunoblot analysis and enzyme assays. Determination of genotypes in blood leucocyte DNA showed that possession of the mu-class GSTM1 gene was closely related to the expression of GSTM1-1 and GSTM3-3 enzymes in lung cytosol: patients with the GSTM1 null genotype had no detectable GSTM1 protein and less GSTM3 protein than patients with the GSTM1 gene (P < 0.001). Absence of the GSTM1 gene did not affect the content of phi-class GSTP1-1 or alpha-class GSTA1/2. GST activity towards 1-chloro-2,4-dinitrobenzene was lower (P < 0.01) in patients lacking the GSTM1 gene than in those expressing GSTM1; in general, patients with a low GSTM3-3, GSTP1-1 or GSTA1/2 content also had significantly less overall GST activity. The pulmonary content of GSTP1-1 was greater in cancer than in non-cancer patients (P < 0.05). Smoking did not influence the levels of GST isozymes or the EH activity. In contrast, the AHH activity was significantly (P < 0.01) increased by smoking. Neither AHH nor EH showed a correlation with GSTM1 polymorphism. Our data support the idea that in smokers who lack the GSTM1 gene, activation of carcinogens in tobacco smoke (e.g. benzo[alpha]pyrene) is increased, while the efficacy of detoxification is limited both qualitatively (absence of GSTM1-1 enzyme and low expression of GSTM3-3 enzyme) and quantitatively (low overall GST activity). This imbalance in the metabolism of carcinogens may explain the increased susceptibility to lung cancer reported in smokers with the GSTM1 null genotype.
Carcinogenesis 1995 Apr
PMID:Expression and polymorphism of glutathione S-transferase in human lungs: risk factors in smoking-related lung cancer. 772 47

The individual genotoxic response of cultured human lymphocytes to diepoxybutane (DEB), an epoxide metabolite of 1,3-butadiene, shows a bimodal distribution. Blood donors can be classified as either DEB-sensitive or DEB-resistant on the basis of the frequency of sister chromatid exchanges (SCEs) induced by DEB in whole-blood lymphocyte cultures. The genetic basis of this phenomenon has thusfar been unknown. To investigate if differences in the ability of individuals to detoxify DEB could explain the bimodal response, sister chromatid exchanges (SCEs) induced by a 48-h treatment with DEB (2 and 5 microM) were analyzed in whole-blood lymphocyte cultures of 20 human donors with known genotypes of two polymorphic glutathione S-transferases (GSTs), GSTT1 and GSTM1. Both polymorphisms include a homozygous null genotype lacking the respective GST gene and isozyme. The mean frequency of SCEs/cell was 1.6 times higher among GSTT1 null donors (n = 8) than GSTT1 positive donors (n = 12) at both 2 microM DEB (mean 67.3 versus 40.9) and 5 microM DEB (mean 123.2 versus 77.5), with no overlapping in DEB-induced individual SCE frequencies between the two genotypes. Thus, all DEB-sensitive individuals were of the GSTT1 null genotype, while all DEB-resistant persons had a detectable GSTT1 gene. A significant (P < 0.05) negative correlation (r = -0.65 at 5 microM, r = -0.56 at 2 microM) was obtained in the GSTT1 positive donors between DEB-induced individual SCE frequency and RBC GSTT1 activity, measured by formaldehyde formation from dichloromethane; the GSTT1 null individuals showed no GSTT1 activity. At 5 microM DEB, the lymphocyte cultures of the GSTT1 null donors also had a significantly decreased replication index, indicating an impact of GSTT1 genotype on the cytotoxicity of DEB. No influence on DEB-induced SCEs or cytotoxic effects was observed for GSTM1 genotype. It is concluded that sensitivity to in vitro SCE induction by DEB is explained by the lack of GSTT1.
Carcinogenesis 1995 Jun
PMID:Role of GSTT1 and GSTM1 genotypes in determining individual sensitivity to sister chromatid exchange induction by diepoxybutane in cultured human lymphocytes. 778 40

Transplacental transfer of genotoxic material has been determined by measuring the polycyclic aromatic hydrocarbon-albumin adduct level in serum isolated from the mother and the umbilical cord using a competitive ELISA assay and the antibody (8E11) against benzo[a]pyrene (B[a]P) tetrols. Smoking women (median 5.54 fmol B[a]P equiv/microgram albumin; 21 cases) and non-smoking women living in rural areas (median 4.99; 30) had higher adduct levels than non-smoking women living in suburbia (median 4.09; 37), whereas non-smoking women living in the city of Aarhus had an intermediate level (median 4.82; 40). Exposure to passive smoking did not modify the adduct levels. When all non-smoking cases were combined, the transport time to/from the home became a major contributing factor to the adduct level. The median adduct level in umbilical cord blood was significantly lower than in maternal blood, the maternal/fetal ratio being approximately 1.3, and a positive association between the adduct levels in the mother and umbilical cord blood was observed. The frequency of the GSTM1 null genotype in the study population, females aged 19-44, was 55.4%, but the GSTM1 genotype did not significantly alter the serum albumin adduct level. This study indicates that the competitive ELISA to detect B[a]P bound to serum albumin is sensitive enough to detect differences in the burden of genotoxic compounds in non-occupational exposed individuals. The lower adduct level in people living in suburbia suggests that local production of incomplete combustion products, like vehicle exhaust or heat generation, is the major contributing factor to genotoxic compounds in the general environment.
Carcinogenesis 1995 Jun
PMID:Transplacental transfer of environmental genotoxins: polycyclic aromatic hydrocarbon-albumin in non-smoking women, and the effect of maternal GSTM1 genotype. 778 47

Genetically based differences in metabolism, related to MspI restriction site and Ile-Val polymorphisms of the cytochrome P450 (CYP) 1A1 gene and the null genotype of glutathione transferase class mu (GSTM1), have been reported to be associated with lung cancer susceptibility. The present study was set up to establish the frequencies of the polymorphic genotypes of CYP1A1 and GSTM1 in Sweden, to evaluate a possible increased incidence of the genotypes associated with higher lung cancer risks among Swedish lung cancer patients and to try to make a combined risk estimate for carriers of multiple risk alleles. In a healthy control group, all under 66 years of age, 53% (174/329) of the subjects were of the GSTM1(-) genotype, while in a hospital control group 49% (39/79) carried the GSTM1(-) genotype. In the investigated lung cancer patients this genotype was found in 56% (165/296) and among those patients diagnosed before 66 years of age the deficient genotype was found in 60% (78/131). The highest proportion of the GSTM1(-) genotype was found in patients diagnosed with adenocarcinoma (63%, 29/46) and small cell carcinoma (72%, 21/29) before 66 years of age and among female squamous cell carcinoma patients (79%, 15/19). The allelic variants in CYP1A1 were equally distributed in lung cancer patients and controls. The m1/m2 and m2/m2 genotypes of the MspI site and the Ile/Val genotype were, however, slightly over-represented in squamous cell carcinoma patients. Among patients with squamous cell carcinoma diagnosed before 66 years of age the m1/m2 genotype was found in 28% (10/36), whereas the same genotype was observed in 16% (52/329) of healthy control subjects. A combined risk of squamous cell carcinoma was indicated for patients, diagnosed before 66 years of age, carrying both GSTM1(-) and m2 alleles (OR = 3.0, 95% CI = 1.2-7.2).
Carcinogenesis 1994 Sep
PMID:Genetic susceptibility to lung cancer with special emphasis on CYP1A1 and GSTM1: a study on host factors in relation to age at onset, gender and histological cancer types. 792 70


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