NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones

Joseph, Pius; Jaiswal, Anil K.

doi:10.1038/bjc.1998.117

Cited by 58 publications

(23 citation statements)

References 30 publications

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“…NQO1 protects the cells from quinone muta- Biotransformation enzymes and breast cancer J Šarmanová et al genicity by competing with one-electron donor P450 reductase, which produces highly reactive semiquinones. 24 Moreover, the frequently used chemotherapy for various tumors by quinone anticancer drugs, anthracyclines (eg doxorubicin, epirubicin), is based on the ability of reduced form to promote apoptosis and bind to DNA -topoisomerase II complex. 25 Carriers of mutant homozygote genotype have no NQO1 activity and thus basic hypothesis regarding these individuals may be drawn: simultaneous lack of the NQO1 activity and exposure to quinones, for example, products of benzene metabolism promotes mutagenesis and carcinogenesis.…”

Section: Resultsmentioning

confidence: 99%

Breast cancer: role of polymorphisms in biotransformation enzymes

et al. 2004

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We aimed at determining whether any association exists between genetic polymorphisms in epoxide hydrolase (EPHX1), NADPH-quinone oxidoreductase (NQO1), glutathione S-transferases (GSTM1/P1/T1) and individual susceptibility to breast cancer. Polymerase chain reaction-restriction fragment length polymorphism-based genotyping assays were used to determine the frequency of polymorphisms in EPHX1 (exons 3 and 4), NQO1 (exon 6), GSTM1 (deletion), GSTP1 (exon 5), and GSTT1 (deletion) in a case -control study comprised of 238 patients with breast cancer and 313 healthy individuals. The distribution of genotypes in exon 6 of NQO1 was significantly different between the control group and breast cancer cases. Age-adjusted odds ratio (OR) for variant genotype NQO1*2/*2 was 3.68 (confidence interval (CI) ¼ 1.41 -9.62, P ¼ 0.008). Association of GSTP1*2/*2 genotype as well as that of low EPHX1 activity deduced by combinations of genotypes in exons 3 and 4 with breast cancer was suggestive, but nonsignificant. Individuals simultaneously lacking GSTM1 and carrying at least one GSTP1 variant allele were at significantly higher risk of breast cancer (OR ¼ 2.03, CI ¼ 1.18 -3.50, P ¼ 0.010). Combinations of either GSTM1null or GSTP1*2 with low activity of EPHX1 presented significant risk of breast cancer (OR ¼ 1.88, CI ¼ 1.00 -3.52, P ¼ 0.049 and OR ¼ 2.40, CI ¼ 1.15 -5.00, P ¼ 0.019, respectively) as well. In conclusion, the results suggest that genetic polymorphisms in biotransformation enzymes may play a significant role in the development of breast cancer.

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Section: Resultsmentioning

confidence: 99%

Breast cancer: role of polymorphisms in biotransformation enzymes

et al. 2004

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“…33,34) Therefore, downregulation of POR expression by SWCNTs could at least partially be involved in the prevention of POR-dependent carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Single-Walled Carbon Nanotubes Downregulate Stress-Responsive Genes in Human Respiratory Tract Cells

Hitoshi

Katoh

Suzuki

et al. 2012

Biological & Pharmaceutical Bulletin

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Carbon nanotubes (CNTs) are currently key promising materials of nanotechnology. However, elucidation of the possible effects of CNTs on the respiratory tract is urgently needed. The present study aimed to clarify the effect of single-walled CNTs (SWCNTs) on the expression of stress-responsive genes, using primary cultured normal human bronchial epithelial (NHBE), diseased HBE (DHBE) cells, and the human carcinoma cell lines A549 and FaDu. Purified SWCNTs were applied at concentrations of 0.1 or 1.0 mg/mL for 6 h, and a polymerase chain reaction (PCR) array was conducted to examine 84 stress-responsive genes. NHBE cell exposure to SWCNTs resulted in global downregulation of genes involved in inflammation, oxidative stress, and apoptosis. Further analysis using DHBE cells and carcinoma cell lines indicated a similar trend, although differences in sensitivity were observed. Downregulation of stress-responsive genes may be involved in the mechanism by which stress response protects against lung injury.Key words carbon nanotube; stress-responsive gene; human bronchial epithelial cell Nanotechnology has drastically emerged over the past 10 years, and a vast variety of nanomaterials, which can be employed in a wide range of applications in nanoscience, medicine, and engineering, have been created. Carbon nanotubes (CNTs), discovered by Iijima, are currently key promising materials of nanotechnology.

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“…Second, the epoxide can enter quinone/semiquinone redox cycling, generating free radicals which can oxidize DNA (30). The end result of both mechanisms is the introduction of specific mutations which may lead to cellular transformation.…”

Section: Discussionmentioning

confidence: 99%

Modulation of Glucose-6-phosphate Dehydrogenase Activity and Expression Is Associated with Aryl Hydrocarbon Resistance in Vitro

Yeh

Daschner

Lopaczynska

et al. 2001

Journal of Biological Chemistry

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The mutagenic effect of environmental carcinogens has been well documented in animal models and in human studies but the mechanisms involved in preventing carcinogen insult have not been fully elucidated. In this study we examined the molecular and biochemical changes associated with carcinogen resistance in a series of aryl hydrocarbon-resistant MCF-7 cell lines developed by exposure to benzo[a]pyrene (BP). The cell lines were designated as AH R40, AH R100, and AH R200 to denote their increasing fold resistance to BP compared with wild type cells. These cell lines were also resistant to another aryl hydrocarbon (AH), dimethylbenz[a]anthracene, but not to pleiotropic drugs (doxorubicin, vinblastine, and taxol). The resistant cell lines showed an increase in the level of the primary intracellular antioxidant, reduced glutathione, corresponding to increasing AH resistance. However, there was no change in glutathione reductase activity. The generation of reduced glutathione requires NADPH, and we therefore examined the activity and expression of the rate-limiting enzyme in NADPH production, glucose-6-phosphate dehydrogenase (G6PD). An increase in G6PD specific activity was associated with increasing aryl hydrocarbon resistance. This was due to an increased expression of G6PD in resistant cells, which was demonstrated by increases in both protein and mRNA levels. However, there was no increase in the transcription rate of G6PD in the resistant cell lines, indicating that the increase G6PD expression is due to a post-transcriptional modulation, which was confirmed by actinomycin D chase experiments. These results demonstrate that modulation of G6PD expression and activity is an important mechanism in AH resistance.

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NAD(P)H:quinone oxidoreductase 1 reduces the mutagenicity of DNA caused by NADPH:P450 reductase-activated metabolites of benzo(a)pyrene quinones

Cited by 58 publications

References 30 publications

Breast cancer: role of polymorphisms in biotransformation enzymes

Breast cancer: role of polymorphisms in biotransformation enzymes

Single-Walled Carbon Nanotubes Downregulate Stress-Responsive Genes in Human Respiratory Tract Cells

Modulation of Glucose-6-phosphate Dehydrogenase Activity and Expression Is Associated with Aryl Hydrocarbon Resistance in Vitro

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