NAD(P)H:Quinone Oxidoreductase 1 (NQO1, DT-Diaphorase), Functions and Pharmacogenetics
Introduction
NQO1 is a flavoprotein that is known to catalyze two electron reduction of a broad range of substrates.1, 2, 3 As the name of the enzyme suggests, a common group of substrates are quinones, which are reduced via a hydride transfer mechanism to generate the corresponding hydroquinone derivative. Elucidation of the mechanism of catalysis has been facilitated by elucidation of the crystal structure of the enzyme and has been recently summarized.4, 5, 6, 7 The broad substrate specificity has also been explained by structural studies demonstrating the presence of a highly plastic active site that can accommodate a range of structures.8 Because of the many deleterious effects of quinonoid compounds, including their capacity to arylate nucleophiles and generate aggressive oxygen species via redox cycling mechanisms, removal of a quinone from a biological system by NQO1 has been considered to be a detoxification reaction.9, 10, 11, 12 Two electron reduction of certain antitumor quinones such as mitomycin C, E09, streptonigrin and B-lapachone by NQO1, however, results in bioactivation of these compounds to more toxic metabolites.13, 14, 15, 16 Since NQO1 is expressed at high levels throughout many human solid tumors,17, 18 compounds efficiently bioactivated by NQO1 have been designed for the therapy of tumors rich in NQO1.8, 19, 20, 21 Currently, a new NQO1-targeted aziridinylbenzoquinone, RH1,20 is undergoing phase 1 clinical trials. The role of NQO1 in chemoprotection and its contrasting role in bioactivation of antitumor quinones22, 23 and both the gene and protein structure of NQO124, 25 have been recently summarized. The purpose of this review is to introduce the enzyme, to review the possible functions of NQO1, to summarize current information on polymorphic forms of NQO1 and finally, to summarize the relevance of the common NQO1∗2 polymorphism for chemoprotection, susceptibility to disease and cancer chemotherapy.
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Early Work on Mitochondrial Electron Transport and Vitamin K Metabolism
When NQO1 was first isolated by Ernster,26, 27 there was considerable controversy regarding a potential role for NQO1 in mitochondrial electron transport. This work was summarized in a fascinating historical review of the enzyme by Ernster in 1987.28 NQO1 was found not to be a component of the mitochondrial respiratory chain, and attention turned to other possible physiological functions for the enzyme such as a potential role in vitamin K metabolism, suggested in the early 1960s by Martius.29
Genotype-Phenotype Relationships
The NQO1∗2 polymorphism was characterized in a collaboration between our own laboratory and that of Dr. Neil Gibson. During investigations of a series of human colon carcinoma cell lines60 and lung tumor cell lines,61 a good correlation was observed between NQO1 mRNA levels and NQO1 activity. In each series of tumor cell lines, however, one cell line (BE human colon carcinoma cells and H596 lung cancer cells) demonstrated high mRNA levels but no NQO1 activity. After SSCP analysis and DNA
Acknowledgements
The authors are supported by NIH grants CA51210, ES09554 and NS44613.
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