Polymorphisms and Pharmacogenomics of NQO2: The Past and the Future.

ABSTRACT

The flavoenzyme N-ribosyldihydronicotinamide (NRH)quinone oxidoreductase 2 (NQO2) catalyzes two-electron reductions of quinones. NQO2 contributes to the metabolism of biogenic and xenobiotic quinones, including a wide range of antitumor drugs, with both toxifying and detoxifying functions. Moreover, NQO2 activity can be inhibited by several compounds, including drugs and phytochemicals such as flavonoids. NQO2 may play important roles that go beyond quinone metabolism and include the regulation of oxidative stress, inflammation, and autophagy, with implications in carcinogenesis and neurodegeneration. NQO2 is a highly polymorphic gene with several allelic variants, including insertions (I), deletions (D) and single-nucleotide (SNP) polymorphisms located mainly in the promoter, but also in other regulatory regions and exons. This is the first systematic review of the literature reporting on NQO2 gene variants as risk factors in degenerative diseases or drug adverse effects. In particular, hypomorphic 29 bp I alleles have been linked to breast and other solid cancer susceptibility as well as to interindividual variability in response to chemotherapy. On the other hand, hypermorphic polymorphisms were associated with Parkinson's and Alzheimer's disease. The I and D promoter variants and other NQO2 polymorphisms may impact cognitive decline, alcoholism and toxicity of several nervous system drugs. Future studies are required to fill several gaps in NQO2 research.