NAD (P) H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin
Long, D.J.; Waikel, R.L.; Wang, X.J.; Roop, D.R.; Jaiswal, A.K.
Journal of the National Cancer Institute 93(15): 1166-1170
2001
ISSN/ISBN: 0027-8874 PMID: 11481389 Document Number: 532345
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 mug in 100 muL of acetone) alone was applied to the shaved 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 applications of phorbol 12-myristate 13-acetate (PMA)-10 mug dissolved in 200 muL 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 mug) 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.