NAD(P)H : quinone Oxidoreductase 1 Deficiency and Increased Susceptibility to 7,12-Dimethylbenz[a]-anthracene-Induced Carcinogenesis in Mouse Skin

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Abstract
Background: The phase II enzyme NAD(P)H : quinone oxidoreductase 1 (NQO1) catalyzes quinone detoxification, protecting cells from redox cycling, oxidative stress, mutagenicity, and cytotoxicity induced by quinones and its precursors. We have used NQO1−/− C57BL/6 mice to show that NQO1 protects them from skin cancer induced by the polycyclic aromatic hydrocarbon benzo[a]pyrene. Herein, we used NQO1−/− mice to investigate whether NQO1 also protects them against 7,12-dimethylbenz[a]anthracene (DMBA), where methyl substituents diminish primary quinone formation. Methods: Dorsal skin of NQO1−/− or wild-type C57BL/6 mice was shaved. When tested as a complete carcinogen, DMBA (500 or 750 μg in 100 μL of acetone) alone was applied to the shaved area. When tested as a tumor initiator, DMBA (200 or 400 nmol in 100 μL of acetone) was applied to the shaved area; 1 week later, twice-weekly applications of phorbol 12-myristate 13-acetate (PMA)—10 μg dissolved in 200 μL of acetone—to the same area began and were continued for 20 weeks. Tumor development was monitored in all mice (12–15 per group). All statistical tests were two-sided. Results: When DMBA (750 μg) was tested as a complete carcinogen, about 50% of the DMBA-treated NQO1−/− mice but no DMBA-treated wild-type mouse developed skin tumors. When DMBA (both concentrations) was used as a tumor initiator, NQO1−/− mice developed larger tumors at a greater frequency than their wild-type littermates. Twenty-three weeks after the first PMA treatment in the tumor initiator test, all 30 NQO1−/− mice given 400 nmol of DMBA had developed skin tumors, compared with 33% (10 of 30) of treated wild-type mice (P<.001). Conclusions: NQO1−/− mice are more susceptible to DMBA-induced skin cancer than are their wild-type littermates, suggesting that NQO1 may protect cells from DMBA carcinogenesis.