NAD(P)H:quinone oxidoreductase (NQO1) polymorphism, exposure to benzene, and predisposition to disease: a HuGE review.
NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two- or four-electron reduction of numerous endogenous and environmental quinones (e.g., the vitamin E alpha-tocopherol quinone, menadione, benzene quinones). In laboratory animals treated with various environmental chemicals, inhibition of NQO1 metabolism has long been known to increase the risk of toxicity or cancer. Currently, there are 22 reported single-nucleotide polymorphisms (SNPs) in the NQO1 gene. Compared with the human consensus (reference, "wild-type") NQO1*1 allele coding for normal NQO1 enzyme and activity, the NQO1*2 allele encodes a nonsynonymous mutation (P187S) that has negligible NQO1 activity. The NQO1*2 allelic frequency ranges between 0.22 (Caucasian) and 0.45 (Asian) in various ethnic populations. A large epidemiologic investigation of a benzene-exposed population has shown that NQO1*2 homozygotes exhibit as much as a 7-fold greater risk of bone marrow toxicity, leading to diseases such as aplastic anemia and leukemia. The extent of the contribution of polymorphisms in other genes involved in the metabolism of benzene and related compounds-such as the P450 2E1 (CYP2E1), myeloperoxidase (MPO), glutathione-S-transferase (GSTM1, GSTT1), microsomal epoxide hydrolase (EPHX1), and other genes-should also be considered. However, it now seems clear that a lowered or absent NQO1 activity can increase one's risk of bone marrow toxicity, after environmental exposure to benzene and benzene-like compounds. In cancer patients, the NQO1*2 allele appears to be associated with increased risk of chemotherapy-related myeloid leukemia. Many other epidemiological studies, attempting to find an association between the NQO1 polymorphism and one or another human disease, have now begun to appear in the medical literature.
Nebert
Daniel W
DW
Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, Ohio 45267-0056, USA.
Roe
Amy L
AL
Vandale
Susan E
SE
Bingham
Eula
E
Oakley
Gregory G
GG
D000483:Alleles; D000818:Animals; D001554:Benzene / Q000009:adverse effects*; D001855:Bone Marrow Diseases / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics*; D004781:Environmental Exposure / Q000009:adverse effects*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length
D016660:NAD(P)H Dehydrogenase (Quinone); D001554:Benzene