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)

NAD(P)H:Quinone oxidoreductase (QR) is a widely-distributed enzyme that promotes obligatory two-electron reductions of quinones and thereby protects cells against the cytotoxicity of quinones and their metabolic precursors. QR is induced by a wide variety of chemoprotectors in many animal tissues as well as in the Hepa 1c1c7 murine hepatoma cell line. Such inducers fall into two families: dual inducers (e.g. polycyclic aromatics, azo dyes, beta-naphthoflavone) that elevate QR as well as cytochrome P1-450, and selective inducers of QR (e.g. tert-butylhydroquinone and other redox-labile diphenols). Induction by the first family of inducers depends on binding to the Ah (Aryl hydrocarbon) receptor and the associated expression of a functional cytochrome P1-450 enzyme, whereas the induction by redox-labile diphenols does not appear to be receptor-mediated. In order to analyze the possible role of the cytochrome P1-450 system in the induction of QR, we examined this process in the Hepa 1c1c7 cells and in four mutants of this cell line that are defective in the induction or expression of functional cytochrome P1-450. tert-Butylhydroquinone was an effective inducer of QR in all of the cell lines, and this process does not, therefore, depend on a functional cytochrome P1-450 enzyme. In contrast, azo dyes and polycyclic aromatics induce QR in the parent cell line but not in the various types of cytochrome P1-450-defective mutants. We conclude that the Ah receptor and cytochrome P1-450 function are involved in the induction of QR by certain azo dyes and polycyclic aromatics, but not by phenolic antioxidants.
Carcinogenesis 1987 Oct
PMID:Role of cytochrome P1-450 in the induction of NAD(P)H:quinone reductase in a murine hepatoma cell line and its mutants. 282 Jun 4

Age-adjusted incidence rates for lung cancer are significantly lower for Hispanics compared with non-Hispanic whites or African-Americans; differences in genetic susceptibility have been postulated as one explanation for these ethnic differences. Recently, a polymorphism of the gene encoding NAD(P)H quinone oxidoreductase (NQO1) has been described. NQO1 is a cytosolic enzyme catalyzing the two-electron reduction of quinone substrates, which is thought to be involved in both metabolic activation and detoxification of carcinogenic agents that could be involved in lung carcinogenesis. The polymorphic variant of the gene (a C-to-T transition at base pair 609) is associated with reduced NQO1 activity and resistance to anticancer agents requiring reductive activation. We studied 177 untreated lung cancer cases and 297 community controls, examining the prevalence of the NQO1 wild-type and variant alleles to assess whether the polymorphism was associated with lung cancer. Cases and controls were individuals of Mexican-American (n = 222) or African. American (n = 252) ethnicity recruited from the Houston and San Antonio areas. Overall cases were more likely to carry two copies of the wild-type NQO1 allele compared with controls (odds ratio, 1.79; P = 0.002). When cases and controls were stratified by ethnicity, the wild-type genotype was found to be approximately 2-fold more common among African-Americans (P < 0.001) than among Mexican-Americans. Multivariate analyses indicated a significant association of the wild-type genotype with lung cancer risk after controlling for the effects of age, gender, ethnicity, and smoking status (odds ratio, 1.80; 95% CI:1.09-2.97; P = 0.02). These results indicate a significant ethnic variation in the occurrence of the NQO1 base pair 609 transition and demonstrate an association of the wild-type genotype with lung cancer risk. Given the known role of NQO1 in the activation of potential lung carcinogens, the NQO1 polymorphism should be investigated further as a possible genetic risk factor for lung cancer among minority populations.
 ...
PMID:Lung cancer in Mexican-Americans and African-Americans is associated with the wild-type genotype of the NAD(P)H: quinone oxidoreductase polymorphism. 903 58

Esophageal cancer has been associated with tobacco smoking, and nitrosamines are possible causative agents for this cancer. The present study investigated the metabolism of the tobacco carcinogens N'-nitrosonornicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and N-nitrosodimethylamine (NDMA), as well as the presence of xenobiotic-metabolizing enzymes in human esophageal tissues from individuals in the United States and Huixian, Henan Province, China (a high-risk area for esophageal cancer). All esophageal microsomal samples activated NNN and the metabolic rate was 2-fold higher in the esophageal samples from China than the USA. All microsomal samples activated NDMA. However, most of the microsomal samples did not activate NNK. Troleandomycin (an inhibitor of cytochrome P450 3A) decreased the formation of NNN-derived keto acid by 20-26% in the esophageal microsomes. The activities for NADPH: cytochrome c reductase, ethoxycoumarin O-deethylase, NAD(P)H: quinone oxidoreductase and glutathione S-transferase were present in the esophageal samples. Coumarin 7-hydroxylase (a representative activity for P450 2A6) activity was not detected in the esophageal microsomal samples. The activities for nitrosamine metabolism and xenobiotic-metabolizing enzymes were decreased (by 30-50%) in the squamous cell carcinomas compared with their corresponding non-cancerous mucosa. The presence of activation and detoxification enzymes in the esophagus may play an important role in determining the susceptibility of the esophagus to the carcinogenic effect of nitrosamines. Our results suggest that P450s 3A4 and 2E1 are involved in the activation of NNN and NDMA, respectively, in the human esophagus.
Carcinogenesis 1998 Apr
PMID:Characterization of xenobiotic-metabolizing enzymes and nitrosamine metabolism in the human esophagus. 960 Mar 53

Most of the chemicals that cause toxicity in animals are metabolized and this metabolism can either increase or decrease the extent of toxicity. A large number of enzymes are involved in the metabolism of xenobiotics. Cytochromes P450 are among the most important and these enzymes are primarily involved in metabolic activation through oxidative metabolism. Transferases, including the glutathione S-transferases, N-acetyltransferases, UDP-glucuronosyltransferases, microsomal and cytosolic epoxide hydrolases, and NAD(P)H quinone oxidoreductase are also significant in xenobiotic metabolism and can play a role in chemical sensitivities. Polymorphisms in P450s and transferases have been found in experimental animals and humans in which a certain segment of the population, usually greater than 1%, are lacking expression of a particular enzyme. In humans, polymorphisms have been associated with adverse drug reactions but have not been shown to cause any serious developmental or physiological defects thus suggesting that in mammals, xenobiotic-metabolizing enzymes may only be required for metabolism of foreign chemicals and have no other critical role. To determine the roles of xenobiotic-metabolizing enzymes in mammalian development and physiological homeostasis, and in sensitivities to chemical toxicity and carcinogenesis, targeted gene disruption was carried out to produce gene knockout mice. Several lines of mice were produced and characterized and these are discussed.
 ...
PMID:The study of xenobiotic-metabolizing enzymes and their role in toxicity in vivo using targeted gene disruption. 1002 49

Glutathione S-transferase GSTM1 B and GSTT1 null, and cytochrome P450 CYP2D6 EM have been associated with cutaneous basal cell carcinoma (BCC) numbers, although their quantitative effects show that predisposition to many BCC is determined by an unknown number of further loci. We speculate that other loci that determine response to oxidative stress, such as NAD(H):quinone oxidoreductase (NQO1) are candidates. Accordingly, we assessed the association between NQO1 null and BCC numbers primarily to rank NQO1 null in a model that included genotypes already associated with BCC numbers. We found that only 14 out of 457 cases (3.1%) were NQO1 null. This frequency did not increase in cases with characteristics linked with BCC numbers including gender, skin type, a truncal lesion or more than one new BCC at any presentation (MPP). However, the mean number of BCC in NQO1*0 homozygotes was greater than in wild-type allele homozygotes and heterozygotes, although the difference was not quite significant (P = 0.06). These data reflect the link between NQO1 null and BCC numbers in the 42 MPP cases rather than the whole case group. We identified an interaction between NQO1 null and GSTT1 null that was associated with more BCC (P = 0.04), although only four cases had this combination. The relative influence of NQO1 null was studied in a multivariate model that included: (i) 241 patients in whom GSTM1 B, GSTT1 null and CYP2D6 EM genotype data were available, and (ii) 101 patients in whom these genotypes, as well as data on GSTM3, CYP1A1 and melanocyte-stimulating hormone receptor (MC1R) genotypes were available. NQO1 null (P = 0.001) and MC1R asp294/asp294 (P = 0.03) were linked with BCC numbers, and the association with CYP2D6 EM approached significance (P = 0.08). In a stepwise regression model only these genotypes were significantly associated with BCC numbers with NQO1 null being the most powerful predictor.
Carcinogenesis 1999 Jul
PMID:Association of NAD(P)H:quinone oxidoreductase (NQO1) null with numbers of basal cell carcinomas: use of a multivariate model to rank the relative importance of this polymorphism and those at other relevant loci. 1038 95

Most chemical carcinogens require metabolic activation to electrophilic metabolites that are capable of binding to DNA and causing gene mutations. Carcinogen metabolism is carried out by large groups of xenobiotic-metabolizing enzymes that include the phase I cytochromes P450 (P450) and microsomal epoxide hydrolase, and various phase II transferase enzymes. It is extremely important to determine the role P450s play in the carcinogenesis and to establish if they are the rate limiting and critical interface between the chemical and its biological activities. The latter is essential in order to validate the use of rodent models to test safety of chemicals in humans. Since there are marked species differences in expressions and catalytic activities of the multiple P450 forms that activate carcinogens, this validation process becomes especially difficult. To address the role of P450s in whole animal carcinogenesis, mice were produced that lack the P450s known to catalyze carcinogen activation. Mouse lines having disrupted genes encoding the P450s CYP1A2, CYP2E1, and CYP1B1 were developed. Mice lacking expression of microsomal epoxide hydrolase (mEH) and NADPH-quinone oxidoreductase (NQO1) were also made. All of these mice exhibit no gross abnormal phenotypes, suggesting that the xenobiotic-metabolizing enzymes have no critical roles in mammalian development and physiological homeostasis. This explains the occurrence of polymorphisms in xenobiotic-metabolizing enzymes among humans and other mammalian species. However, these null mice do show differences in sensitivities to acute chemical toxicities, thus establishing the importance of xenobiotic metabolism in activation pathways that lead to cell death. Rodent bioassays using null mice and known genotoxic carcinogens should establish whether these enzymes are required for carcinogenesis in an intact animal model. These studies will also provide a framework for the production of transgenic mice and carcinogen bioassay protocols that may be more predictive for identifying the human carcinogens and validate the molecular epidemiological studies ongoing in humans that seek to establish a role for polymorphisms in cancer risk.
 ...
PMID:Understanding the role of xenobiotic-metabolism in chemical carcinogenesis using gene knockout mice. 1137 89

Inactivation of the p16(INK4a) tumor suppressor gene and O(6)-methylguanine-DNA methyltransferase (MGMT) DNA repair gene by aberrant promoter methylation appears to be an important step in respiratory carcinogenesis after exposure to tobacco smoke and radon progeny. The determinants of aberrant promoter methylation are not well characterized. Polymorphic variants of genes of which the products are involved in pathways that modulate and repair DNA damage after carcinogen exposure may affect the occurrence of de novo promoter methylation. On the basis of their associations with risk of lung cancer, we hypothesized that functional polymorphic variants of the NADPH quinone oxidoreductase, glutathione S-transferases P1 and M1, myeloperoxidase, and XRCC1 genes are associated with p16 and/or MGMT promoter methylation in sputum from cancer-free subjects at high risk for developing lung cancer. This hypothesis was tested by conducting a cross-sectional study of 70 former uranium miners from the Uranium Epidemiological Study cohort who were at high risk for lung cancer. The polymorphic variant genotypes were characterized through PCR-RFLP on DNA isolated from peripheral lymphocytes, and the methylation status of the p16 and MGMT promoters was determined by methylation-specific PCR on DNA isolated from sputum. Subjects who had at least one GSTP1 polymorphic allele (A-to-G at bp 104) had an increased risk for MGMT methylation [odds ratio (OR), 4.8; 95% confidence interval (CI), 1.2-18.6] or for either p16 or MGMT methylation (OR, 4.4; 95% CI, 1.3-14.2). Lack of a wild-type NADPH quinone oxidoreductase allele (C at bp 609) was also associated with methylation of either p16 or MGMT (OR, 3.1; 95% CI, 1.0-9.2). These results provide the first link between germ-line functional deficits in pathways that protect the cell from tobacco- and radon-induced DNA damage, and the development of aberrant promoter methylation of the p16 and MGMT genes in the respiratory epithelium of individuals at high risk for lung cancer.
 ...
PMID:Glutathione S-transferase P1 and NADPH quinone oxidoreductase polymorphisms are associated with aberrant promoter methylation of P16(INK4a) and O(6)-methylguanine-DNA methyltransferase in sputum. 1195 78

Acrolein, an alpha,beta-unsaturated aldehyde, is by far the strongest electrophile present in cigarette smoke which is involved in several lung pathophysiological conditions. Acrolein depletes glutathione and creates thiol imbalance. Acrolein due to thiol imbalance as well as covalent modification of cysteine is known to inhibit the activity of redox sensitive transcription factors such as NF-kappaB and AP-1. Exposure of human type II lung epithelial (A549) cells to non-lethal dose of acrolein (150 fmol/cell for 1 h) depletes 80% of intracellular glutathione and increases the transcription of gamma-glutamylcysteine synthetase (gamma-GCS) at 6-12 h post-treatment, which helps in replenishing the glutathione to normal level. Acrolein treatment activates transcription of phase II genes in general, as indicated by an increase in mRNA for NAD (P) H:quinone oxidoreductase (NQO1). Western blot analysis revealed the increased level of the transcription factor, Nrf2 in the nuclear extract from acrolein treated cells. Electrophoretic mobility shift assay shows increased binding of nuclear proteins to human antioxidant response element (ARE) consensus sequence after treatment with acrolein. The involvement of Nrf2 in ARE mediated transcriptional activation in response to acrolein exposure has been confirmed by human NQO1-ARE reporter assay. The ability of acrolein to transcriptionaly activate genes responsible for phase II enzymes may form the basis of resistance against cell death and can have implications in cigarette smoke related lung carcinogenesis.
 ...
PMID:Acrolein causes transcriptional induction of phase II genes by activation of Nrf2 in human lung type II epithelial (A549) cells. 1208 17

Dihydronicotinamide riboside (NRH):quinone oxidoreductase 2 (NQO2) is a flavoenzyme that catalyzes the reductive metabolism of quinones. To examine the in vivo role of NQO2, NQO2-null (NQO2-/-) mice were generated using targeted gene disruption. Mice lacking NQO2 gene expression showed no detectable developmental abnormalities and were indistinguishable from wild-type (NQO2+/+) mice. However, NQO2-null mice exhibited myeloid hyperplasia of the bone marrow and increased neutrophils, basophils, eosinophils, and platelets in the peripheral blood. Decreased apoptosis of bone marrow cells and circulating granulocytes contributed to myeloid hyperplasia and hyperactivity of bone marrow in NQO2-null mice. The hematological changes in NQO2-/- mice were specifically associated with loss of the NQO2 gene because histological analysis of various tissues including spleen, thymus, blood cultures, and urine analysis demonstrated no sign of infection. NQO2-null mice also demonstrated decreased toxicity when exposed to menadione or menadione with NRH. These results establish a role for NQO2 in protection against myelogenous hyperplasia and in metabolic activation of menadione, leading to hepatic toxicity. The NQO2-null mice are a model for NQO2 deficiency in humans and can be used to determine the role of this enzyme in sensitivities to toxicity and carcinogenesis.
 ...
PMID:Disruption of dihydronicotinamide riboside:quinone oxidoreductase 2 (NQO2) leads to myeloid hyperplasia of bone marrow and decreased sensitivity to menadione toxicity. 1235 51

Human exposure to arsenic, a ubiquitous and toxic environmental pollutant, is associated with an increased incidence of skin cancer. However, the mechanism(s) associated with AsIII-mediated toxicity and carcinogenesis at low levels of exposure remains elusive. Aberrations in cell proliferation, oxidative damage, and DNA-repair fidelity have been implicated in sodium arsenite (AsIII)-mediated carcinogenicity and toxicity, but these events have been examined in isolation in the majority of biological models of arsenic exposure. We hypothesized that the simultaneous interaction of these effects may be important in arsenic-mediated neoplasia in the skin. To evaluate this, normal human epidermal keratinocytes (NHEK) were exposed to nontoxic doses (0.005-5 micro M) of AsIII and monitored for several physiological endpoints at the times when cells were harvested for gene expression measurements (1-24 h). Two-fluor cDNA microarray analyses indicated that AsIII treatment decreased the expression of genes associated with DNA repair (e.g., p53 and Damage-specific DNA-binding protein 2) and increased the expression of genes indicative of the cellular response to oxidative stress (e.g., Superoxide dismutase 1, NAD(P)H quinone oxidoreductase, and Serine/threonine kinase 25). AsIII also modulated the expression of certain transcripts associated with increased cell proliferation (e.g., Cyclin G1, Protein kinase C delta), oncogenes, and genes associated with cellular transformation (e.g., Gro-1 and V-yes). These observations correlated with measurements of cell proliferation and mitotic measurements as AsIII treatment resulted in a dose-dependent increase in cellular mitoses at 24 h and an increase in cell proliferation at 48 h of exposure. Data in this manuscript demonstrates that AsIII exposure simultaneously modulates DNA repair, cell proliferation, and redox-related gene expression in nontransformed, normal NHEK. It is anticipated that data in this report will serve as a foundation for furthering our knowledge of AsIII-regulated gene expression in skin and other tissues and contribute to a better understanding of arsenic toxicity and carcinogenesis.
 ...
PMID:Coordination of altered DNA repair and damage pathways in arsenite-exposed keratinocytes. 1237 79


1 2 3 4 5 Next >>