Benzene, NQO1, and genetic susceptibility to cancer

NAD(P)H:quinone oxidoreductase 1 (NQO1; EC 1.6.99.2), originally called DT-diaphorase (1), is an enzyme that has attracted considerable attention because of its ability to detoxify a number of natural and synthetic compounds and, conversely, to activate certain anticancer agents (2, 3). It is also a highly inducible enzyme. Synthetic antioxidants, such as butylated hydroxyanisole, and extracts of cruciferous vegetables, including broccoli, have been shown to be potent inducers of NQO1 (4, 5). This inducibility has led to the suggestion that NQO1 plays an important role in cancer chemoprevention (6).

In 1980, Edwards et al. (7) reported that 4% of a British population completely lacked NQO1 activity, but the reasons for and implications of this finding were unclear at the time. In the early 1990s, as part of their studies on the bioactivation of quinone anticancer agents, Ross, Gibson, and their colleagues were characterizing the NQO1 activities of various colon and lung carcinoma cell lines (8). They noticed that two of the lines, the BE colon carcinoma line and the nonsmall cell lung cancer H596 cell line, were different in that they showed no demonstrable NQO1 activity. By using DNA sequencing analysis, they established the presence of a homozygous C to T point mutation at position 609 of the NQO1 cDNA from the BE cell line (8). This mutation conferred a proline-to-serine substitution at position 187 of the NQO1 protein, which they suggested was responsible for the lack of NQO1 activity in BE cells. Sequencing of the coding region of NQO1 from lung H596 cells subsequently showed the presence of the identical homozygous point mutation found in BE cells (9). Thus, the lack of NQO1 activity in certain cell lines and subjects in the Edwards et al. study was most likely the result of homozygous inheritance of two mutant …