NAD(P)H: quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]anthracene-induced carcinogenesis in mouse skin

Background: The phase 11 enzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) cat alyzes quinone detoxification, protecting cells from redox cycling, oxidati ve stress, mutagenicity, and cytotoxicity induced by quinones and its precu rsors. We have used NQO1(-/-)C57BL/6 mice to show that NQO1 protects them f rom skin cancer induced by the polycyclic aromatic hydrocarbon benzo[a]pyre ne. Herein, we used NQO1(-/-) mice to investigate whether NQO1 also protect s them against 7,12-dimethylbenz[a]anthracene (DMBA), where methyl substitu ents 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 mug in 100 muL of acetone) alone was applied to the shave d area. When tested as a tumor initiator, DMBA (200 or 400 nmol in 100 muL of acetone) was applied to the shaved area; 1 week later, twice-weekly appl ications of phorbol 12-myristate 13-acetate (PMA)-10 mug dissolved in 200 m uL 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 t ests were two-sided. Results: When DMBA (750 mug) was tested as a complete carcinogen, about 50% of the DMBA-treated NQO1(-/-) mice but no DMBA-treate d wild-type mouse developed skin tumors. When DMBA (both concentrations) wa s used as a tumor initiator, NQO1(-/-) mice developed larger tumors at a gr eater frequency than their wildtype littermates. Twenty-three weeks after t he first PMA treatment in the tumor initiator test, all 30 NQO1(-/-) mice g iven 400 nmol of DMBA had developed skin tumors, compared with 33% (10 of 3 0) of treated wild-type mice (P < .001). Conclusions: NQO1(-/-) mice are mo re susceptible to DMBA-induced skin cancer than are their wild-type litterm ates, suggesting that NQO1 may protect cells from DMBA carcinogenesis.