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)

Animal and human studies on aryl hydrocarbon hydroxylase (AHH) have demonstrated wide inter-individual variation. First attempts to link this variation to the susceptibility to certain cancers have been successful in mice but remained inconclusive in man. In a new approach, saliva antipyrine half-lives and metabolic clearance rates have been used to assess individual rates of benzo]a]pyrene metabolism in human subjects. Saliva antipyrine half-lives and metabolic clearance rates have been measured in 57 patients with lung cancer, 90% of whom had quit smoking more than three months prior to the test, 57 cancer-free matched controls, and 59 healthy smoking controls. The mean antipyrine half-life was significantly shorter (P less than 0.001) in lung cancer patients when compared with the cancer-free matched control group, but differed little from that of the smoking group (P less than 0.05). The data support the previous observation than lung cancer patients have increased oxidation rates which, in addition to smoking, might have predisposed them to developing lung cancer.
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PMID:Variation of microsomal mixed function oxidase(s) and human lung cancer. 735 25

A new technique has been used for culturing human keratinocytes. The cells grow on the basement membrane-like capsules of bovine lenses. Lens cells were removed from the capsules by rigid trypsinization. In order to exclude any contamination with remaining living cells the isolated capsules were irradiated with X-rays at a dose of 10,000 rad. In this way human epithelial cells can be brought in culture from individual hair follicles. Since feeder cells are not used in this culture technique, the biosynthesis of keratinocyte proteins can be studied in these cultures. The newly synthesized proteins can be separated into a water-soluble, a urea-soluble, and a urea-insoluble fraction. Product analysis has been performed on the first two fractions revealing protein patterns identical to those of intact hair follicles. Product analysis of the urea-soluble fractions of microdissected hair follicles shows that the protein pattern of the cultured keratinocytes resembles the protein pattern of the hair follicle sheath. Studies on the metabolism of benzo(a)pyrene revealed that the enzyme aryl hydrocarbon hydroxylase (AHH) is present in cultured hair follicle cells. A possible use of our culture system for eventual detection of inherited predisposition for smoking-dependent lung cancer is discussed.
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PMID:Protein biosynthesis in cultured human hair follicle cells. 744 61

The Ah receptor (Ahr) is a ligand-dependent transcription factor that positively regulates inducible expression of the CYP1A1 gene. Based on the sequence information of the human Ahr and the intron-exon junctions of the mouse counterpart, an analysis of single-strand conformational polymorphism (SSCP) was carried out to detect subtle base differences in the coding region of the gene among individuals. We found that the Ahr protein has at least two forms of variants in a Japanese gene pool, and that these variants can be ascribed to one amino acid replacement of Arg by Lys at codon 554. The frequencies of Arg-coded and Lys-coded alleles were 0.57 and 0.43, respectively. We found, however, that this germ line polymorphism of the Ahr gene did not show a significant association with aryl hydrocarbon hydroxylase (AHH) inducibility nor with lung cancer incidence.
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PMID:Polymorphisms of human Ah receptor gene are not involved in lung cancer. 755 Mar 66

Polycyclic aromatic hydrocarbon-DNA adducts were measured by ELISA in peripheral leukocytes from 119 non-small cell lung cancer patients and 98 controls at the Columbia-Presbyterian Medical Center. Thirty-one cases had adduct measurements in leukocytes, lung tumor, and nontumor specimens collected at surgery, and 34 had paired leukocyte and tumor specimens. Information on smoking, diet, and occupational exposure was collected. After adjustment for age, gender, ethnicity, season, and smoking, adducts in leukocytes were significantly higher in cases (P < 0.01) than controls; the odds ratio was 7.7 (95% confidence interval = 1.7-34; P < 0.01). Adducts in leukocytes were increased significantly in smokers and ex-smokers compared to nonsmokers among cases and controls (separately and combined) after adjusting for age, gender, ethnicity, and season (P < 0.05). The cases and controls differed in several respects: (a) adducts increased with the number of cigarettes smoked among the 51 cases who were current smokers (P = 0.05) but not among the current smokers in the controls; and (b) a seasonal variation in DNA binding, corresponding to that reported for aryl hydrocarbon hydroxylase inducibility, was observed in cases but not in controls. Among the cases, adducts in leukocytes were correlated more strongly with adducts in the lung tumor tissue than with those in nontumor lung tissue. The results in leukocytes are consistent with a constitutional susceptibility to lung cancer, which results in greater DNA damage from carcinogens in cigarette smoke. They suggested that it may ultimately be possible to use biomarkers such as adducts to identify individuals who would benefit most from early intervention.
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PMID:A molecular epidemiological case-control study of lung cancer. 765 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.
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PMID:Expression and polymorphism of glutathione S-transferase in human lungs: risk factors in smoking-related lung cancer. 772 47

In order to investigate the relationship between aryl hydrocarbon hydroxylase (AHH) activity and smoking or lung cancer, AHH activities in fresh lungs (normal tissue, tumorous tissue, and surrounding tissue of tumor) obtained from lung cancer patients and non-lung cancer patients were measured. There were no differences in lung AHH activity in the lung lobes. In the non-lung cancer patients, AHH activities ranged from 0.13 to 2.37 (pmol 3 hydroxybenzo[a]pyrene/20 min/mg protein), and whereas in the normal tissues of the lung cancer patients they ranged from 0.19 to 5.05. Lung AHH activities showed normal distribution, and a large variation (26 times) was observed in normal tissues in the lung cancer patients. In most cases, AHH activities in the tumorous tissues and the surrounding tissue of the tumor were lower than those in the normal tissues of the lung cancer patients. In the non-lung cancer group, the means of AHH activity of the nonsmoker subgroup (NN) and the smoker subgroup (SN) were 0.62 and 0.96, respectively. On the other hand, in the lung cancer group the means of AHH activity of the nonsmoker subgroup (NC) and smoker subgroup (SC) were 0.85 and 1.05, respectively. Statistically significant differences were observed between NN and SN, NN and NC, and NN and SC. These results suggest that human lung AHH activity was increased by cigarette smoke as in rodent lungs, and the distribution of basal AHH activity in lung tissue of the nonsmokers group in the lung cancer patients shifted toward high levels compared to the nonsmokers group in the non-lung cancer group. The effect of the histological cell types of the lung cancer on the AHH activity was not observed in this study.
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PMID:Aryl hydrocarbon hydroxylase activity in human lung tissue: in relation to cigarette smoking and lung cancer. 816 76

Exposure to benzopyrene, an enzyme-inducing PAH carcinogen, promotes vitamin A depletion in exposed tissues. This effect is evident while on a vitamin A sufficient diet and without a decline in serum retinol. The finding of local tissue vitamin depletion without systemic depletion may have considerable implications in maintaining tissue health. While the described studies involved dietary exposure to benzopyrene, it is reasonable to extrapolate that inhalation exposure via cigarette smoke would have a similar effect in the lungs and perhaps stomach and bladder. Higher MFO enzyme activity in the lungs may have detrimental effects. Kellermann's early work identifying a higher incidence of lung cancer in those with genetically greater aryl hydrocarbon hydroxylase activity was interpreted as due to the greater formation of a reactive intermediate in the process of carcinogen metabolism. As an alternative hypothesis I suggest that those with higher enzyme inducibility may have greater carcinogen-induced vitamin A depletion. If poor tissue vitamin A nutriture potentiates the carcinogenicity of compounds such as benzopyrene, dietary or pharmacologic interventions which improve tissue nutriture could be important. The demonstrated effect of dietary beta-carotene on preventing carcinogen-induced tissue vitamin A depletion suggests one mechanism by which beta-carotene may be cancer protective. Further investigations are warranted, particularly with inhalation exposure to carcinogens and the effect of dietary beta-carotene on lung tissue nutriture.
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PMID:Carcinogen-induced tissue vitamin A depletion. Potential protective advantages of beta-carotene. 851 48

We examined the relationship between aryl hydrocarbon hydroxylase (AHH) and the frequency of a MspI mutation in the 3'-flanking region of cytochrome P450 (CYP) 1A1 (MspI polymorphism) and another mutation in exon 7 (Ile-Val polymorphism) in 84 healthy male subjects in Fukuoka, Japan. AHH inducibility (3-methylcholanthrene (MC)-induced AHH activity/non-induced AHH activity) was correlated with the MspI polymorphism (P < 0.0001) and age class (P = 0.015), whereas no correlation was found for the Ile-Val polymorphism (P = 0.509). Age-adjusted AHH inducibility (mean +/- SE) of the predominant homozygote (genotype A), the heterozygote (genotype B) and a homozygote rare allele (genotype C) genotypes was 4.89 +/- 0.36, 4.82 +/- 0.29 and 13.61 +/- 1.44, respectively. The genotype C showed much higher AHH inducibility than genotypes A and B (P < 0.001), while no significant difference was observed between genotypes A and B. Non-induced AHH activity was also correlated with these polymorphisms. The AHH activity of a homozygous mutant Val/Val genotype (0.076 +/- 0.010 pmol/min/10(6) cells) was significantly higher (P < 0.05) than that of the wild-type homozygous Ile/Ile (0.044 +/- 0.004 pmol/min/10(6) cells) and heterozygous Ile/Val (0.047 +/- 0.007 pmol/min/10(6) cells) genotypes. Our study suggests that the genotypes C and Val/Val, which are more frequent in smoking-related lung cancer, are closely related with high AHH inducibility and high non-induced AHH activity, respectively. Thus, the positive relationship between AHH inducibility and lung cancer is supported by our study. If our results are confirmed and the assessment of genotype becomes feasible on a population basis, identification of smokers who have genetically high susceptibility to lung cancer (genotype C or Val/Val) may become important for the prevention of lung cancer.
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PMID:The relationship between aryl hydrocarbon hydroxylase and polymorphisms of the CYP1A1 gene. 860 43

Since aryl hydrocarbon hydroxylase (AHH) is considered to be responsible for the activation of benzo(a)pyrene (BP) and other polyaromatic hydrocarbons in cigarette smoke to carcinogens, it is important to examine AHH activity in the determination of susceptibility to lung cancer. Lymphocytes from healthy male adults (239) of non-smokers and smokers were cultured in vitro and assayed for non-induced and 3-methylcholanthrene (MC)-induced AHH activity and AHH inducibility (MC-induced AHH activity/non-induced AHH activity). A day-to-day variation in AHH activity was not observed while a seasonal variation was apparent. Very wide differences in non-induced AHH and MC-induced AHH activities were observed. The association of some selected environmental factors and AHH activity was studied. Age was related to non-induced AHH activity (Spearman's rank correlation coefficients (r), r = 0.185, p < 0.005) and AHH inducibility (r = -0.329, p < 0.001). Coffee consumption was associated with non-induced (age-adjusted r = 0.138, p < 0.05) and MC-induced AHH activity (age-adjusted r = 0.173, p < 0.01). Cigarette smoking was correlated with non-induced AHH activity (age-adjusted r = 0.191, p < 0.005) and AHH inducibility (age-adjusted r = -0.191, p < 0.005). No significant association was observed for any other selected factors, including alcohol intake or broiled food consumption. In conclusion, AHH activity might be affected by cigarette smoking and coffee consumption, and was dependent on the age of the donor. Day-to-day and seasonal variation analyses showed that this assay method was reproducible and reliable and AHH inducibility might be a useful biomarker in cancer epidemiology. As those factors may affect the AHH activity, a careful control of those factors to AHH activity is necessary in epidemiological studies on the association between AHH inducibility in human lymphocytes and lung cancer.
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PMID:Environmental factors and aryl hydrocarbon hydroxylase activity (CYP1A1 phenotype) in human lymphocytes. 946 51

The mechanisms that underly the regulation of human CYP1A1 have merited considerable attention because of their association both with toxic outcomes and the etiology of several cancers. Previous work conducted in this laboratory has identified a negative regulatory element (NRE) in the 5' region of this gene that appeared to modulate CYP1A1 transcriptional activity. This NRE is present in two functional copies, a high affinity 21-bp palindrome centered at position -784, and an additional element found within a GC-rich region between position -728 and -558. In this report, the regulatory function of the NREs in the context of the CYP1A1 promoter was evaluated. This was accomplished by substituting mutated elements for the corresponding wild-type element in a vector that contained human CYP1A1 sequences positions -1140 to +59 directing the transcription of the chloramphenicol acetyltransferase reporter gene. Expression vectors containing specific mutations in each or both NREs were characterized. We show that eliminating the binding of the CYP1A1 repressor protein to one or both repressor motifs results in a significant 2- to 3-fold increase in the inducibility of CYP1A1 promoter activity. Although mutation of both sites appeared to result in an increase in inducibility over that observed with only one site mutated, the effect was not additive. Such aberrant transcriptional activity correlates with the highly inducible aryl hydrocarbon hydroxylase phenotype that is a reported marker for individuals predisposed to lung cancer. Mutation of the NRE, or more likely, the cognate repressor protein(s), may provide a genetic basis for this phenotype.
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PMID:Functional characterization of the human CYP1A1 negative regulatory element: modulation of Ah receptor mediated transcriptional activity. 963 62


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