UMLS:C0242379 - FACTA Search

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Query: UMLS:C0242379 (lung cancer)
71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pattern of expression of individual cytochrome P450 (CYP) forms participating in the metabolism of xenobiotics is being increasingly well characterised in the human pulmonary tissue. Recent studies using methods having increased sensitivity and specificity, such as the reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, have revealed constitutive and inducible expression of several CYP forms in different cell types of the human lung. These studies have revealed the presence of mRNA of several procarcinogen-activating CYP forms in whole lung tissue and alveolar macrophages, including CYP1A1, CYP2B6/7, CYP2E1, and CYP3A5. The results of several studies on CYP2D6 expression have yielded contradictory results. Immunohistochemical analysis shows that CYP3A5 protein is present in all lung samples studied, and is localized in the ciliated and mucous cells of the bronchial wall, bronchial glands, bronchiolar ciliated and terminal cuboidal epithelium, type I and type II alveolar epithelium, vascular and capillary endothelium, and alveolar macrophages. Also CYP3A4 protein is found in some cell types in a minority (about 20%) of lung samples. Primary cultures of freshly isolated broncho-alveolar macrophages as well as a continuously growing bronchial carcinoma cell line (A-549) are being used for CYP induction studies in our laboratory. The results indicate that CYP1 family members are inducible in these cells by polycyclic aromatic hydrocarbon (PAH) inducers, and that CYP3A5, but not CYP3A4, is present constitutively. The results of these studies indicate that several different xenobiotic-metabolizing CYPs are present in the human lung and lung-derived cell lines, possibly contributing to in situ activation of pulmonary procarcinogens. Interindividual differences in the expression of these CYPs may contribute to the risk of developing lung cancer and possibly other pulmonary diseases initiated by agents that require metabolic activation.
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PMID:Expression of xenobiotic-metabolizing CYPs in human pulmonary tissue. 1044 7

Many investigators have reported an association between genetic polymorphisms of cytochromes P-450 CYP2E1, CYP1A1 or glutathione S-transferase Mu (GSTM1) and susceptibility to lung cancer. However, pronounced interethnic variations have been described in the frequencies of these polymorphisms, especially between Asians and Caucasians. The present study was set up to establish CYP2E1 (c1, c2 and C, D), CYP1A1 (m1, m2 and Ile, Val) and GSTM1 (null) allelic frequencies in Chileans (n = 96) who are an admixture of Native Americans and Caucasians (Spaniards). The rare allele frequencies were found to be 0.15 (c2), 0.21 (C), 0.23 (m2), 0.32 (Val) and 0.21 ('null' genotype). These values are significantly higher than those of Caucasians except for the GSTM1 'null' genotype and suggest differences in susceptibility to lung cancer between both populations.
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PMID:Ethnic susceptibility to lung cancer: differences in CYP2E1, CYP1A1 and GSTM1 genetic polymorphisms between French Caucasian and Chilean populations. 1045 58

Metabolism of most chemical carcinogens in humans is thought to occur in two distinct phases. The carcinogens exert their effect only after being metabolically activated to intermediates (phase I), which are capable of binding to DNA and causing mutations. The most ubiquitous phase I catalysts are the cytochrome P450s (CYPs). There is convincing epidemiological evidence that lung cancer risk associated with polycyclic aromatic hydrocarbons (PAHs) is mediated in part by aryl hydrocarbon hydroxylase (AHH), which is used as an indicator of the phenotype of CYP1A1. Since AHH is responsible for the activation PAHs in cigarette smoke, it may be important in the causation of lung cancer. Kellermann et al. reported a significant positive correlation between AHH inducibility and susceptibility to lung cancer. The finding, however, has been both supported and refuted by subsequent investigators. Advances in molecular biology have allowed many allelic variants of several drug metabolizing enzymes so that individuals with the susceptible genotypes can be determined easily. A close association between development of lung cancer and homozygous rare genotypes in MspI and Ile-Val polymorphisms of CYP1A1 gene has been recently reported in some Japanese populations. The association between GSTM1 polymorphism and lung cancer risk is not so strong, however. Following the phase I reaction, phase II enzymes such as glutathione S-transferases (GSTs) are responsible for detoxification of activated forms PAH-epoxides. GSTs form a superfamily of genes consisting of four distinct families, named Alpha, Mu, Pi and Theta. The GSTM1, GSTT1 and GSTP1 genes are polymorphic in humans. The phenotypic absence of GSTM1 activity is due to a homozygous inherited deletion of the gene, the null genotype. The homozygous deletion of GSTM1 genes has been shown to occur in approximately 50% of the populations of various ethnic origins. The GSTM1 null genotype confrs a moderately increased risk of smoking-related lung cancer, however. Genetically determined susceptibility to lung cancer may depend on the metabolic balance between phase I and phase II enzymes. Risk of lung cancer, especially squamous cell carcinoma is shown to be remarkably increased in individuals with a combination of a homozygous rare allele of the CYP1A1 gene and the nulled GSTM1 gene, compared with those having other combinations of genotypes. Individuals with susceptible genotypes may become important for the prevention of lung cancer.
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PMID:[Role of metabolic polymorphisms in lung carcinogenesis]. 1049 56

Many case-control studies on the role of detoxifying enzyme polymorphisms in susceptibility to cancer have identified significant associations, though few have identified effects with sufficient strength to be useful clinically. Odds ratios of 2-3 are the usual finding. Therefore, combinations of risk alleles are increasingly studied in the hope of identifying haplotypes with sufficient biological impact (odds ratio > 15) to warrant further study in a clinical setting. The study of interactions between different detoxifying enzyme loci should be based on biological sense, for example the classical view of two-step xenobiotic detoxification, overlapping substrate specificities, detoxification of molecules derived from the same pathological insult (e.g. detoxification of nitrosamines and polycyclic aromatic hydrocarbons in cigarette smoke) or simultaneous regulation of expression. The rationale behind these mechanisms is discussed. Considerable amounts of data have focused on the interaction between CYP1A1 and GSTM1, particularly in Japanese patients with lung cancer. In this regard there is accumulating evidence suggesting that the combination of GSTM1 null/CYP1A1 rare alleles, particularly in combination with smoking, confers highly significant increased risk. However, there is now some debate on the importance of these data in terms of chemical detoxificatlon, since certain studies suggest that the CYP1A1 polymorphisms that have been investigated do not influence function or expression of the gene. Indeed, the influence of CYP2D6 genetic variation is also disputed, suggesting that these polymorphisms may be acting more as linkage markers than by influencing chemical carcinogenesis themselves. What is clear from the many studies on interactions between detoxifying enzyme polymorphisms is the comparative lack of supporting data on synergism between these genes. Given the inevitable increase in the complexity of studies, a basic explanation of the statistical approaches to the assessment of interactions is included in this chapter. A more detailed statistical/epidemiological assessment is given elsewhere in the book. Since there is an increasing reluctance of journals to publish case-control studies describing the (usually moderate) influence of detoxifying enzyme polymorphisms, it is important that scientists understand what statistical approach is appropriate and address the issue from a novel and clinically significant angle. This is likely to involve multiple genes and subgroup analysis of some kind.
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PMID:Interactions between detoxifying enzyme polymorphisms and susceptibility to cancer. 1049 64

The CYP and GST genetic polymorphisms, controlling metabolism of xenobiotics, are considered to influence an individual's susceptibility to environmental and occupational carcinogens and predisposition to cancer. In the study, the effect of the GSTM1, GSTP1, CYP1A1 and CYP2D6 polymorphisms was investigated in relation to PAH-DNA adduct levels in non-tumourous lung tissue from non-small cell lung cancer (NSCLC) patients living in the industrialized region of Upper Silesia, Poland. The level of adducts among smokers was significantly elevated when compared to non-smokers (P = 0.0005). Adduct levels correlated inversely with age of patients (P = 0.00001). The GSTP1 and CYP2D6 polymorphisms had no influence on DNA adduct levels. There was a significant relationship between high adduct levels and the combined GSTM1 (null)/CYP1A1-Ile/Val genotype in the squamous cell carcinoma group (P = 0.028). An elevated number of adducts was found in patients with the GSTM1 (null)/CYP1Al-Ile/Val genotype compared to the GSTM1 (null)/CYP1A1-Ile/Ile carriers (P = 0.043). A higher frequency of the CYP1A1-Ile/Val and GSTM1 (null)/CYP1A1-Ile/Val genotypes was observed in patients with high adduct levels (P = 0.05 and P = 0.009, respectively). A significant prevalence of the GSTM1(null)/CYP1A1-Ile/Val carriers in the adenocarcinoma group was found (P = 0.003). Thus, our findings imply that the GSTMI and CYP1A1 exon 7 polymorphisms may influence PAH-DNA adduct levels in target tissue from NSCLC patients, especially in the squamous cell carcinoma group. Moreover, individuals carrying the GSTM1(null)/CYP1A1-Ile/Val genotype might exhibit a greater predisposition to a peripheral type of lung cancer.
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PMID:GSTM1, GSTP1, CYP1A1 and CYP2D6 polymorphisms in lung cancer patients from an environmentally polluted region of Poland: correlation with lung DNA adduct levels. 1049 7

Direct epidemiological observations suggest that exposure to high levels of urban air pollution may result in increased risk of lung cancer, sufficient to account for a few (approximately 1-3) percent of total lung cancer incidence. Extrapolation from occupational exposure and risk data suggests that among potential carcinogens present in polluted urban air, polycyclic aromatic hydrocarbons (PAHs) may make a major contribution to air pollution-associated lung cancer risks. The use of biomarkers of genotoxocity in large-scale population studies may help to reduce the uncertainty involved in the assessment of such risks, especially those associated with relatively low pollution levels such as nowadays found in many Western cities. Increases in biomarkers of exposure to urban air PAHs as well as biomarkers of early effects have been detected in situations of relatively high levels of air pollution (e. g., ambient PAH concentrations of the order of a few tens of micrograms per cubic meter). Evidence has also been found about the modulation genetic damage accumulation in different individuals by polymorphisms in genes involved in the activation or detoxification of PAHs, especially of polymorphisms GSTM1 and CYP1A1 genes. However, the inconsistencies in the currently reported effects of genetic polymorphisms suggest that additional factors may also be important in the modulation of individual susceptibility to the accumulation of PAH-derived genetic damage. Biomarkers studies in populations exposed to relatively low ambient PAH concentrations (below 20 microg/m(3)) have not demonstrated clear dose-related effects (e.g., on DNA adduct levels), possibly because of the existence of multiple sources and routes of human exposure to PAHs in addition to inhalation of urban air (including, for example, home heating, environmental tobacco smoke and diet), and the consequent difficulty of adequately and specifically assessing atmospheric air-related exposure. This makes it imperative that molecular epidemiology studies be designed in such a way as to allow adequate assessment of exposure to urban air PAHs at the individual level and over short-, medium- and long-term time periods which correspond to the expression times of different biomarkers.
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PMID:Molecular epidemiological approaches to the study of the genotoxic effects of urban air pollution. 1051 82

Preventive strategies require identification of cancer-susceptible individuals resulting from combinations of carcinogen exposure, cancer-predisposing genes, and lack of protective factors. To this aim, related to tobacco smoking and chewing (betel quid), we measured PAH-DNA adducts as exposure and susceptibility markers together with genetic polymorphism in drug-metabolizing enzymes related to CYP1A1, GSTM1, and GSTT1 genes in case-control studies. (+)-anti-Benzo(a)pyrene diol-epoxide (BPDE)-DNA adduct levels were quantitated in white blood cells (WBCs) and lung tissue DNA. CYP1A1 polymorphism and GSTM1 or GSTT1 gene deletion was analyzed in genomic DNA from lung parenchyma, WBCs, or oral biopsies (leukoplakia patients from India) and from oral exfoliated cells (healthy controls). Results from lung cancer patients and PAH-exposed coke oven workers correlated CYP1A1-GSTM1 genotype combinations with BPDE-DNA adduct levels. Smokers with homozygous CYP1A1 variant and GSTM1 null had the highest adduct levels and were, as shown in Japanese smokers, most susceptible to lung cancer. In oral premalignant leukoplakia cases associated with betel quid/tobacco chewing, the prevalence of the GSTM1 null and GSTT1 null genotypes was significantly higher, as compared to healthy controls. The combined GST null genotypes prevailed in 60% of the cases with none detected in controls. Based on this short review we conclude that (i) BPDE-DNA adduct levels resulting from "at risk" genotype combinations may serve as markers to identify most susceptible individuals; (ii) in Indian betel quid/tobacco chewers, the null genotypes of GSTM1 and GSTT1 greatly increased the risk for developing oral leukoplakia.
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PMID:Genetic cancer susceptibility and DNA adducts: studies in smokers, tobacco chewers, and coke oven workers. 1057 54

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.
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PMID:Modulation of benzo[a]pyrene diolepoxide-DNA adduct levels in human white blood cells by CYP1A1, GSTM1 and GSTT1 polymorphism. 1060 31

Most carcinogenic substances require metabolic activation in order to become ultimate carcinogens. Genetic polymorphism of xenobiotic metabolising enzymes cytochromes P450 may therefore influence human cancer susceptibility. The aim of our study was to investigate if CYP1A1 gene polymorphism contributes to lung cancer susceptibility in Slovenian patients. Two polymorphic sites in CYP1A1 gene were analysed in DNA samples from 100 healthy controls and 199 lung cancer patients using genotyping approach. Our results indicate that CYP1A1 may be one of the factors determining susceptibility to squamous cell carcinoma of lung in Slovenian population. However the frequency of CYP1A1 polymorphisms is too low to be a potentially useful marker of increased lung cancer risk.
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PMID:Genetic polymorphism of xenobiotic metabolising enzymes in Slovenian lung cancer patients. 1065 31

Lung cancer is the leading cause of death among cancers in Taiwan. Although the etiology of lung cancer has yet to be defined, genetic variability in activities of metabolic enzymes has been correlated with lung cancer. In the present study, the possibility of association of CYP1A1 and microsomal epoxide hydrolase (HYL1) genetic polymorphisms with lung cancer was examined among 132 lung cancer patients and 259 controls in Taiwan. No significant association was observed for either CYP1A1 or HYL1 polymorphism alone and the overall incidence of lung cancer after adjusting for age, gender and smoking status. When cases were stratified according to histological type, there was significant association between CYP1A1*2A homozygote and squamous cell carcinoma (SCC) (odds ratio (OR) 2.86; 95% confidence interval (CI) 1.33-6.12). Similarly, the proportion of HYL1 genotypes corresponding to high or normal enzyme activities was higher in SCC than in controls (OR 1.96; 95% CI 1.04-3.70). A combination of susceptible CYP1A1 and HYL1 genotypes was found to be highly associated with lung cancer, especially with SCC (OR 6.76; 95% CI 2.29-19.10). Our results suggest that the combination of CYP1A1 and HYL1 polymorphisms is an important risk factor for lung SCC.
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PMID:Association of CYP1A1 and microsomal epoxide hydrolase polymorphisms with lung squamous cell carcinoma. 1073 58

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