Quinone oxidoreductases in protection against myelogenous hyperplasia and benzene toxicity

https://doi.org/10.1016/j.cbi.2005.03.019Get rights and content

Abstract

Quinone oxidoreductases (NQO1 and NQO2) are cytosolic proteins that catalyze metabolic reduction of quinones and its derivatives to protect cells against redox cycling and oxidative stress. In humans, a high percentage of individuals with myeloid and other types of leukemia are homo- and heterozygous for a null mutant allele of NQO1. The NQO2 locus is also highly polymorphic in humans. Recently, we generated NQO1−/− and NQO2−/− mice deficient in NQO1 and NQO2 protein and activity, respectively. These mice showed no detectable developmental abnormalities and were indistinguishable from wild type mice. Interestingly, all the mice lacking expression of NQO1 and NQO2 protein demonstrated myelogenous hyperplasia of the bone marrow and increased granulocytes in the peripheral blood. Decreased apoptosis contributed to myelogenous hyperplasia. The studies on short-term exposure of NQO1−/− mice to benzene demonstrated substantially greater benzene-induced toxicity, as compared to wild type mice.

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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