NAD(P)H:quinone oxidoreductase 1 deficiency and increased susceptibility to 7,12-dimethylbenz[a]-anthracene-induced carcinogenesis in mouse skin.
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 microg in 100 microL of acetone) alone was applied to the shaved area. When tested as a tumor initiator, DMBA (200 or 400 nmol in 100 microL of acetone) was applied to the shaved area; 1 week later, twice-weekly applications of phorbol 12-myristate 13-acetate (PMA)-10 microg dissolved in 200 microL 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 microg) 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.
Long
D J
DJ
Department of Pharmacology, Baylor College of Medicine, Houston, TX, USA.
Waikel
R L
RL
Wang
X J
XJ
Roop
D R
DR
Jaiswal
A K
AK
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D002273:Carcinogens; D004198:Disease Susceptibility / Q000201:enzymology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011808:Quinone Reductases / Q000172:deficiency*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology*
D002273:Carcinogens; D015127:9,10-Dimethyl-1,2-benzanthracene; D011808:Quinone Reductases