The NQO1 allelic frequency in hindu population of central India varies from that of other Asian populations

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Abstract

CONTEXT:

The enzymes encoded by the polymorphic genes NAD (P) H: quinone oxidoreductase 1 ( NQO1) play an important role in the activation and inactivation of xenobiotics. This enzyme has been associated with xenobiotic related diseases, such as cancer, therapeutic failure and abnormal effects of drugs.

AIM:

The aim of the present study was to determine the allelic and genotypic frequencies of NQO Hinf I polymorphisms in a Hindu population of Central India.

SETTINGS AND DESIGN:

Polymorphisms of NQO1 were determined in 311 unrelated Hindu individuals.

MATERIALS AND METHODS:

Polymerase chain reaction- Restriction Fragment Length Polymorphism (PCR-RFLP) analysis in peripheral blood DNA for NQO1 Hinf I polymorphism was used in 311 unrelated Hindu individuals.

STATISTICAL ANALYSIS:

Allele frequencies were calculated by direct counting. Hardy Weinberg Equilibrium was evaluated using a Chi-square goodness of fit test.

RESULTS:

The observed allelic frequency was 81% for C (wild) and 19% for T (mutant) in the total sample.

CONCLUSIONS:

The allelic frequency of “C” was higher than in other Asians (57%), but similar to Caucasians (81%). The genotype distributions for Hinf I polymorphisms were in Hardy-Weinberg equilibrium.

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Most cited references 27

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NQO1 stabilizes p53 through a distinct pathway.

Y Shaul, Joel L Sachs, Joseph Lotem … (2002)

Wild-type p53 is a tumor-suppressor gene that encodes a short-lived protein that, upon accumulation, induces growth arrest or apoptosis. Accumulation of p53 occurs mainly by posttranslational events that inhibit its proteosomal degradation. We have reported previously that inhibition of NAD(P)H: quinone oxidoreductase 1 (NQO1) activity by dicoumarol induces degradation of p53, indicating that NQO1 plays a role in p53 stabilization. We now have found that wild-type NQO1, but not the inactive polymorphic NQO1, can stabilize endogenous as well as transfected wild-type p53. NQO1-mediated p53 stabilization was especially prominent under induction of oxidative stress. NQO1 also partially inhibited p53 degradation mediated by the human papilloma virus E6 protein, but not when mediated by Mdm-2. Inhibitors of heat shock protein 90 (hsp90), radicicol and geldanamycin, induced degradation of p53 and suppressed p53-induced apoptosis in normal thymocytes and myeloid leukemic cells. Differences in the effectiveness of dicoumarol and hsp90 inhibitors to induce p53 degradation and suppress apoptosis in these cell types indicate that NQO1 and hsp90 stabilize p53 through different mechanisms. Our results indicate that NQO1 has a distinct role in the regulation of p53 stability, especially in response to oxidative stress. The present data on the genetic and pharmacologic regulation of the level of p53 have clinical implications for tumor development and therapy.

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Regulation of genes encoding NAD(P)H:quinone oxidoreductases.

A Jaiswal (2000)

NAD(P)H:quinone oxidoreductase (NQO1) and NRH:quinone oxidoreductase (NQO2) are flavoproteins that catalyze two-electron reduction and detoxification of quinones and its derivatives. This leads to the protection of cells against redox cycling, oxidative stress, and neoplasia. NQO1 is expressed ubiquitously in all the tissues. However, the level of expression varied among the human tissues. NQO1 gene is expressed at higher levels in several tumor tissue types, including liver and colon, as compared to normal tissues of similar origin. NQO1 gene expression is coordinately induced with other detoxifying enzyme genes in response to xenobiotics, antioxidants, oxidants, heavy metals, and radiations. Deletion mutagenesis in the NQO1 gene promoter identified several cis-elements including antioxidant response element (ARE), a basal element, and AP-2 element. ARE elements have also been found in the promoter regions of other detoxifying enzyme genes including glutathione S-transferases. ARE is essentially required for expression and coordinated induction of NQO1 and other detoxifying enzyme genes. Nuclear transcription factors Nrf2 and c-Jun bind to the ARE and activate the gene expression. The binding of Nrf2 + c-Jun to the ARE required unknown cytosolic factor(s). In addition to Nrf2 and c-Jun, other nuclear transcription factors including Nrf1, Jun-B, and Jun-D also bind to the ARE and regulate expression and induction of NQO1 gene. A hypothetical model is presented based on the available information on ARE-mediated regulation of detoxifying enzyme genes. Briefly, the Nrf2 is retained in the cytosplasm by a repressor protein Keap1 in untreated normal cells. The treatment of cells with xenobiotics and antioxidants leads to the activation of unknown cytosolic factor(s) that catalyze modification of Nrf2 and/or Keap1. The modification follows dissociation of Nrf2 and Keap1. The free Nrf2 translocates in the nucleus. Nrf2 in the nucleus heterodimerizes with c-Jun and binds to the ARE resulting in the induction of NQO1 and other ARE-regulated genes expression. The identity of cytosolic factor(s) remains unknown.

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Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase).

R. D. Traver, J D Siegel, H. D. Beall … (1997)

NAD(P)H:quinone oxidoreductase (NQO1, EC 1.6.99.2) is an obligate two-electron reductase that can either bioactivate or detoxify quinones and has been proposed to play an important role in chemoprevention. We have previously characterized a homozygous point mutation in the BE human colon carcinoma cell line that leads to a loss of NQO1 activity. Sequence analysis showed that this mutation was at position 609 of the NQO1 cDNA, conferring a proline to serine substitution at position 187 of the NQO1 enzyme. Using polymerase chain reaction (PCR) analysis, we have found that the H596 human non-small-cell lung cancer (NSCLC) cell line has elevated NQO1 mRNA, but no detectable enzyme activity. Sequencing of the coding region of NQO1 from the H596 cells showed the presence of the identical homozygous point mutation present in the BE cell line. Expression and purification of recombinant wild-type and mutant protein from E. coli showed that mutant protein could be detected using immunoblot analysis and had 2% of the enzymatic activity of the wild-type protein. PCR and Northern blot analysis showed moderate to low levels of expression of the correctly sized transcript in the mutant cells. Immunoblot analysis also revealed that recombinant mutant protein was immunoreactive; however, the mutant protein was not detected in the cytosol of either BE or H596 cells, suggesting that the mutant proteins were either not translated or were rapidly degraded. The absence of any detectable, active protein, therefore, appears to be responsible for the lack of NQO1 activity in cells homozygous for the mutation. A polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis for the mutation at position 609 conducted on 90 human lung tissue samples (45 matched sets of tumour and uninvolved tissue) revealed a 7% incidence of individuals homozygous for the mutation, and 42% heterozygous for the mutation. These data suggest that the mutation at position 609 represents a polymorphism in an important xenobiotic metabolizing enzyme, which has implications for cancer therapy, chemoprevention and chemoprotection. Images Figure 1 Figure 2 Figure 3

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Author and article information

Journal

Journal ID (nlm-ta): Indian J Hum Genet

Journal ID (publisher-id): IJHG

Title: Indian Journal of Human Genetics

Publisher: Medknow Publications (India )

ISSN (Print): 0971-6866

ISSN (Electronic): 1998-362X

Publication date (Print): Sep-Dec 2010

Volume: 16

Issue: 3

Pages: 133-137

Affiliations

School of Environmental Biology, Awdhesh Pratap Singh University, Rewa 486 003, Madhya Pradesh, India

Author notes

Address for correspondence: Dr. Chauhan, U. K., School of Environmental Biology, Awdhesh Pratap Singh University, Rewa - 486 003, Madhya Pradesh, India. E-mail: ssparihar2001@ 123456yahoo.co.uk

Article

Publisher ID: IJHG-16-133

DOI: 10.4103/0971-6866.73403

PMC ID: 3009423

PubMed ID: 21206700

SO-VID: 2db11e5b-e63f-45ea-8998-ed689c47c09e

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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The NQO1 allelic frequency in hindu population of central India varies from that of other Asian populations

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Abstract

CONTEXT:

AIM:

SETTINGS AND DESIGN:

MATERIALS AND METHODS:

STATISTICAL ANALYSIS:

RESULTS:

CONCLUSIONS:

Related collections

Cancer Biology & Medicine

Most cited references 27

NQO1 stabilizes p53 through a distinct pathway.

Regulation of genes encoding NAD(P)H:quinone oxidoreductases.

Characterization of a polymorphism in NAD(P)H: quinone oxidoreductase (DT-diaphorase).

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