Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytosolic glutathione S-transferases (GSTs) are a supergene family of dimeric enzymes capable of detoxifying a number of carcinogenic electrophiles. Of the numerous components of tobacco smoke, the polycyclic aromatic hydrocarbons appear to be the principal compounds that yield substrates for these enzymes, GSTM1-1 being effective with those PAH derivatives so far studied; however, the gene locus for GSTM1 is polymorphic, containing two well-characterized expressing genes and a null allele. Use of cDNA for GSTM1-1 or appropriate fragments of genomic clones as probes in Southern blots indicated that the null allele is due to the absence of GSTM1. In preliminary experiments, described here, with lung tissue from smokers, levels of 32P-postlabeled nuclease P1-enhanced DNA adducts were inversely correlated with levels of antigen cross-reacting with antibody to GSTM1-1, suggesting that initiation depends on the expression of GSTM1-1. Since similar quantities of DNA adducts and GSTM1-1 activity have been shown to occur in bronchial and peripheral lung, however, the development of malignancy, which is usually in the bronchial region, presumably depends on additional factors that bring about promotion and progression, which are not necessarily affected by GSTM1 expression. Two epidemiological studies have been carried out in which a possible correlation between the absence of GSTM1 and lung cancer incidence is considered. In the first, involving a U.S. population sample, smokers with and without lung cancer were phenotyped, and a highly significant correlation between the absence of GSTM1-1 activity and adenocarcinoma of the lung was observed.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The human glutathione S-transferase supergene family, its polymorphism, and its effects on susceptibility to lung cancer. 148 68

This review on air pollution and lung cancer recapitulates the main issues in this field (urban-rural-gradients; experimental data and occupational epidemiology of exposure to PAH; smoking and occupation as confounders). Definite risk increases have been observed in the vicinity of point emission sources. Within Switzerland lung cancer shows an urban/rural gradient in both sexes. The geographical distribution of the male cases can hardly be explained only by the patterns of smoking alone.
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PMID:[Air pollution and lung cancer]. 242 2

There is a causal correlation between the inhaled dose of asbestos at the working place, the occurrence of asbestosis, and a 5-fold increased mortality rate of lung cancer. Mesothelioma, which appears to be very rare among the general population, is a specific sign of exposure to asbestos fibres. Malignant tumours of the urinary bladder, the gastro-intestinal tract, the larynx and the oesophagus in workers may also be ascribed to the specific exposure in some cases. After a brief outline of the epidemiology of these diseases the carcinogenic effects of asbestos on the cellular and subcellular level are described. It can be shown from most recent literature that asbestos fibres can also trigger epigenetic and genotoxic effects. Numeric mutation of chromosomes, damage of the plasma membrane, and a modification of the immune system are most significant. In the presence of PAH, asbestos acts as a cocarcinogen. Asbestos fibres are positive in the cellular transformation test. Due to its initiating and promoting effects, asbestos proves to be a complete carcinogen. Obviously, asbestos fulfils the criteria of the modern theory of carcinogenesis as a multicausal and multistep process.
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PMID:[The carcinogenic effect of asbestos]. 253 13

The inhalable particles in high and low incidence area of lung cancer in Xuanwei country were extracted with dichloromethane. The extract was separated into aliphatics, PAH, N-PAH, H-PAH, polar compounds by neutral aluminum oxide column chromatography. Mutagenicity and carcinogenicity of different fraction were studied in the Ames test and Two-stage skin carcinogenesis test. The results suggested that the indoor air pollutants in high incidence area showed higher carcinogenicity, higher percentage of PAH fraction and methylated PAH. Ames test showed PAH, N-PAH, H-PAH were active fractions, the N-PAH fraction has maximal mutagenicity. Two-stage skin carcinogenesis test showed the PAH fraction has the highest carcinogenicity, followed by the N-PAH fraction. The results indicated the main carcinogenic fraction and carcinogens of indoor air pollutions in high incidence area of lung cancer in Xuanwei country.
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PMID:[Carcinogenicity and organic fraction of indoor inhalable particles]. 262 51

Rats and mice were exposed to a PAH-rich emission to test the carcinogenic activity. The BaP content of the exposure atmosphere was only 2-3 times higher than the concentration of about 30 micrograms/m3 measured in older coke plants. Although only half of the rats exposed to the exhaust have been investigated histologically up to now, the lung cancer incidence already amounts to 11%, no lung tumours were found in the control animals. Also the mice exposed to the exhaust with and without additional treatment with BaP, DBahA or urethane to induce a "base tumour rate" in the lung, showed a clear exhaust exposure-related carcinogenic effect. The lung tumour multiplicity as well as the incidence was significantly higher. The epidemiological findings of an increased lung cancer risk in coke oven workers can now be supported by the results of this animal inhalation study.
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PMID:Lung tumours in rats and mice after inhalation of PAH-rich emissions. 369 26

Finland is used as a model in attempts to study the possible association of the incidence of lung cancer and exposure of population to fossil fuel combustion products. Unfortunately because of great geographical variation of unknown origin in the incidence of lung cancer in Finland, detailed studies of the possible role of an individual exposure in the lung cancer risk are not possible. This background variation in the incidence is much greater than variation carried by any known etiological factor and does not clearly correlate with the degree of urbanization, industrialization, regional use of fossil fuels, number of motor vehicles or smoking habits. To get more precise information on the possible association of lung cancer incidence with exposure to fossil fuel combustion products, occupational studies serve as powerful tools. The definition of population is more reliable and the measurement of exposures can be done more precisely; moreover the management of confounding and modifying factors is more effective than in community studies. So far the studies carried out among the Finnish working population exposed to PAH compounds reveal an association between the lung cancer risk and exposure to PAHs.
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PMID:Community and occupational studies of lung cancer and polycyclic organic matter. 633 29

A case-control study on lung cancer patients demonstrated the pronounced effect of tobacco smoke on pulmonary carcinogen metabolism and suggested the existence of a metabolic phenotype at higher risk for tobacco-associated lung cancer. Lung cancer patients who were recent smokers showed in their lungs (i) significantly induced CYP1A1-related enzyme activity vs smoking non-lung cancer patients; (ii) increased benzo(a)pyrene (BP) tetrol formation from BP 7,8-diol by lung microsomes; and (iii) high levels of cytochrome P4501a1 by immunohistochemical staining. Levels of bulky aromatic DNA adducts (by 32P-postlabelling) and of BP-diol-epoxide (BPDE) adducts (by HPC/fluorometry) were quantified in lung parenchyma. Aryl hydrocarbon hydroxylase activity and the level of BPDE-DNA adducts (r = 0.91; p < 0.001) and to a lesser degree bulky DNA adducts were correlated. Thus pulmonary CYP1A1 expression (inducibility) controls in part polycyclic aromatic hydrocarbon-DNA adduct formation in tobacco smokers and, therefore, appears to be associated with lung cancer risk. High risk subjects for lung cancer among smokers may be identifiable through genotyping for polymorphic drug metabolizing enzymes in combination with molecular dosimetry of carcinogen-DNA adducts and mutation analysis in target (surrogate) cells. Such studies in a Finnish cohort of lung cancer patients and controls are in progress. Interim results of the effect of metabolic polymorphism on the level of PAH-DNA adducts and on the excretion of mutagens in urine are summarized.
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PMID:Metabolic polymorphism affecting DNA binding and excretion of carcinogens in humans. 758 96

Epidemiological studies have shown an increased incidence of lung cancer, bladder cancer, and esophageal cancer in chimney sweeps, probably due to their exposure to PAH in soot. The work environment for sweeps has, however, improved during the last decades. It was thus important to assess whether the present exposure still may cause genotoxic effects. A further objective was to assess whether genetic polymorphisms in metabolic enzyme activities could explain some of the variation in the parameters of genotoxicity. Venous blood samples were drawn from 71 chimney sweeps and 59 control subjects. Micronuclei were analyzed in activated peripheral B- and T-lymphocytes with preserved cytoplasm. Polymorphisms for CYP1A1 and GST1 in the sweeps were analyzed by a PCR technique. The sweeps did not have higher frequencies of micronuclei in B- or T-lymphocytes than the control subjects, when allowance was made for age and smoking in a multiple regression analysis. Further, there was no association between years of active work as a sweep and any of the two micronucleus parameters. None of the sweeps had the rare CYP1A1 genotype val/val and only one individual had the m2/m2 genotype. The presence of at least one GST1 allele (GST1+) was observed in 36 subjects (51.4%). Thirteen individuals (18.6%) were of the m1/m2 or m2/m2 genotype. And among those only seven had the combined GST1- and m1/m2 genotype. No difference was observed in B- or T-lymphocyte micronucleus frequencies between sweeps with the rare CYP1A1 genotypes m1/m2, m2/m2 or ile/val compared to individuals with the m1/m1 and ile/ile genotypes. Moreover, the GST1 deficient sweeps (GST1-) did not show any altered micronucleus frequency compared to the GST1 positive sweeps. A possible reason for the lack of genotoxic effect in sweeps is the improved hygienic conditions and change in fuels, which has decreased the exposure levels for PAH. Host polymorphisms for metabolizing enzymes did not influence the micronucleus frequencies. As the sweeps did not differ from the control subjects, with respect to micronucleus frequencies, no conclusion on the importance of host polymorphisms for genotoxic risk can be drawn.
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PMID:B- and T-lymphocyte micronuclei in chimney sweeps with respect to genetic polymorphism for CYP1A1 and GST1 (class Mu). 769 Aug 87

The background of regulatory limit values for carcinogenic agents in Sweden is discussed and exemplified with the ambient and occupational air pollutants benzene and PAH (especially benzo[a]pyrene, BaP), ionizing radiation, and radon. The estimated cancer risks at different limit values are compared, as is the estimated number of cancer cases annually due to existing pollutant levels. Although the individual lifetime cancer risks are much higher at the occupational limit values for benzene and BaP than what is recommended for the general public, the estimated number of cancer cases annually is lower at existing pollutant levels. The individual cancer risk at the occupational dose limit for ionizing radiation is comparable to the occupational cancer risk with BaP, but higher than the one for benzene. At the dose limit for the general public, the radiation risk would be higher than what is recommended for individual air pollutants. However, doses from man-made radiation are usually much lower than the dose limit due to optimization. Thus, the estimated number of cancer cases annually due to radiation is low and comparable to the estimated number due to the chemical air pollutants discussed. In contrast, the lung cancer risk with radon in dwellings both at limit values and existing levels is high and comparable to occupational limits for the chemical carcinogens and for radiation. The estimated number of cancer cases annually at existing radon concentrations (1100 cases) is much higher than for the other discussed pollutants (0.03-7 cases each) and also higher than the estimated number of lung cancer cases due to total air pollution (approximately 100 cases).
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PMID:Risk comparisons between limit values for ionizing radiation, PAH, and benzene in Sweden. 812

A survey of the working conditions at a Danish slag wool production factory during the early technological phase in the 1940s is presented. No exposure data, however, are available for that period. So, a full-scale simulation of the past production of slag wool has been performed. Air monitoring was carried out in the working area around the cupola furnace. The aim was to measure exposure to air pollutants other than fibres. Such exposure might have confounded a possible association between lung cancer and exposure to fibres, in the early technological phase of slag wool production. The simulation experiment demonstrated exposure to PAH, a known lung carcinogen. The effect of other concurrent exposures is difficult to assess. Time-weighted average concentrations of particulate material ranged between 12.9 and 49.1 mg m-3 at the upper decks around the cupola. Corresponding concentrations of the dominant metals zinc and lead were 4.4-22.7 mg Zn m-3 and 0.9-4.7 mg Pb m-3. Significant concentrations of PAH up to 269 micrograms PAH m-3 (4 micrograms BaP m-3) occurred during ignition of the cupola furnace. The carbon monoxide level reached 270 ppm also during ignition.
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PMID:Simulation of past exposure in slag wool production. 837 19


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