Quinone oxidoreductases in protection against myelogenous hyperplasia and benzene toxicity
Section snippets
Quinone oxidoreductases (NQO1 and NQO2)
Quinone oxidoreductases [NAD(P)H:quinone oxidoreductase 1 (NQO1) and NRH:quinone oxidoreductase 2 (NQO2)] are cytosolic proteins that catalyze metabolism of quinones and their derivatives [1], [2], [3], [4], [5]. The cytosolic NQO1 activities, purified from rat liver and human adipose tissue, have been characterized and cloned [6], [7], [8], [9], [10], [11]. The dicoumarol sensitive NQO1 is a cytosolic protein of 274 amino acid residues (molecular weight 30,880). NQO1 catalyzes the two-electron
NQO1 and NQO2 gene polymorphism and susceptibility to leukemia
The human NQO1 gene has been localized to chromosome 16q22 [48]. A cytosine to thymidine (C → T) polymorphism in exon 6 of the human NQO1 gene produces a proline to serine (P187S) substitution that destabilizes and inactivates the enzyme [49], [50] (Fig. 1). The mutant NQO1 is rapidly degraded via ubiquitination and proteasome degradation [50]. Individuals carrying both mutated genomic alleles are completely lacking in NQO1 activity, whereas individuals who are heterozygous with one mutated
Myeloid hyperplasia in NQO1−/− and NQO2−/− mice
The structure of the mouse NQO1 gene is reported in Fig. 2[73]. Like the human NQO1 gene, the mouse NQO1 gene contains six exons interrupted by five introns (compare Fig. 1, Fig. 2). The splice junctions and nucleotide sequences in the various exons were highly conserved between the human and mouse genes. Homologous recombination and ES cells were used to replace exon 6 with neomycin cassette as shown in Fig. 2[73]. This generated NQO1−/− mice deficient in NQO1 RNA, protein and activity in
Benzene toxicity and benzene-induced leukemia in NQO1−/− and NQO2−/− mice
Benzene has commonly been used as an industrial solvent, a starting material for the synthesis of other chemicals, and as an antiknock agent in gasoline [77], and is a significant component of cigarette smoke [78]. Benzene is metabolically activated to cause toxic and carcinogenic effects. Benzene is metabolized by cytochrome P450 CYP2E1 to benzene oxide, which spontaneously forms phenol [77] (Fig. 5). Phenol is converted to hydroquinone by P4502E1 [78]. Hydroquinone and related metabolites are
Increased susceptibility of NQO1−/− and NQO2−/− mice to benzo[a]pyrene (BP)- and 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis
We used skin carcinogenesis initiation and initiation/promotion models to determine the sensitivity of NQO1−/− and NQO2−/− mice to development of skin tumors when exposed to environmental chemical carcinogens BP and DMBA [90], [91], [92]. The results demonstrated significantly increased susceptibility of NQO1−/− and NQO2−/− mice to BP and DMBA induced skin carcinogenesis. This was clearly evident by increased frequency and number of tumors per mouse in case of NQO1−/− and NQO2−/− mice as
Future perspectives
The various studies suggest that NQO1 and NQO2 proteins are endogenous factors that protect against myelogenous hyperplasia. The studies also suggest a role of NQO1 and NQO2 against primary and therapy-induced secondary leukemia. However, further experiments are required to determine this.
Acknowledgements
We are thankful to our colleagues from Baylor College of Medicine, Houston, Texas, for valuable suggestions. This work was supported by NIH grants RO1 CA81057, RO1 ES07943 and RO1 GM47644.
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Interactions of the antioxidant enzymes NAD(P)H: Quinone oxidoreductase 1 (NQO1) and NRH: Quinone oxidoreductase 2 (NQO2) with pharmacological agents, endogenous biochemicals and environmental contaminants
2021, Chemico-Biological InteractionsCitation Excerpt :So, there are remarkable differences in inhibitor specificity between NQO1 and NQO2 [29]. Although, reviews over the past decade have described NQO1 mobility [8], polymorphisms [30–32], gene regulation [15,16,31,33], structure [34], distribution [35], sensitivity and resistance [36], functions [13,35,37–39], cytoprotection [39–41], cancer and cardiovascular diseases [25,33,42], no study has reviewed the interaction of NQO1 and NQO2 with specific pharmacological agents, endogenous biochemicals, and environmental contaminants. Thus, we focused on the interactions of NQO1 and NQO2 with different pharmacological agents, endogenous biochemicals, and environmental contaminants that would be relevant towards therapeutic approaches, adverse drug reactions, and protection against quinone-induced oxidative damage.
Regulation: Quinone reductase 2: From classical role in detoxification to emerging role as a novel regulator of cellular activities
2021, Encyclopedia of Biological Chemistry: Third EditionRapid generation of hydrogen peroxide contributes to the complex cell death induction by the angucycline antibiotic landomycin E
2017, Free Radical Biology and MedicineCitation Excerpt :This makes one electron reduction by intracellular flavoenzymes like NADPH oxidase, nitric oxide synthase, xanthine oxidase, and cytochrome P450 reductase unlikely [25,46]. However, there are also several cytosolic proteins involved in the reduction of quinone-containing drugs – namely NQO1 and NQO2 [47,48]. NQO1 has been shown to be the main target of β-lapachone – a novel anticancer ortho-quinone drug, which realizes its cytotoxic activity via ROS production [49] – while NQO2 was found to be associated with menadione-mediated hydrogen peroxide production possessing the same para-quinone core as LE [50].
Chemopreventive effects of standardized papaya leaf fraction on oxidatively stressed human liver cells
2014, Food Research InternationalCitation Excerpt :All these metabolites possessed antioxidant properties (Oberle, Schwartz, Abate, & Schroder, 1999; Otterbein & Choi, 2000; Yesilkaya, Altinayak, & Korgun, 2000) with anti-apoptotic, anti-proliferative and anti-inflammatory actions (Otterbein, Soares, Yamashita, & Bach, 2003). The other highly transcribed gene, nqo-1, was a metabolic enzyme responsible for the detoxification of xenobiotics and the excretion of reactive metabolites (Iskander & Jaiswal, 2005). Therefore, induction of these two chemopreventive proteins indeed fortified the cellular endogenous defense system against oxidative stress.
Chemopreventive effects of standardized papaya leaf fraction on oxidatively stressed human liver cells
2014, Food Research InternationalCitation Excerpt :All these metabolites possessed antioxidant properties (Oberle, Schwartz, Abate, & Schroder, 1999; Otterbein & Choi, 2000; Yesilkaya, Altinayak, & Korgun, 2000) with anti-apoptotic, anti-proliferative and anti-inflammatory actions (Otterbein, Soares, Yamashita, & Bach, 2003). The other highly transcribed gene, nqo-1, was a metabolic enzyme responsible for the detoxification of xenobiotics and the excretion of reactive metabolites (Iskander & Jaiswal, 2005). Therefore, induction of these two chemopreventive proteins indeed fortified the cellular endogenous defense system against oxidative stress.
Induction of quinone oxidoreductase 1 enzyme by Rhazya stricta through Nrf2-dependent mechanism
2012, Journal of Ethnopharmacology