NAD(P)H:quinone oxidoreductase 1 deficiency increases susceptibility to benzo(a)pyrene-induced mouse skin carcinogenesis.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoprotein that catalyzes the metabolic detoxification of quinones and their derivatives. This protects cells against quinone-induced oxidative stress, cytotoxicity, and mutagenicity. C57BL6 NQO1-/- mice, deficient in NQO1 RNA and protein, were generated in our laboratory. To investigate the role of NQO1 in chemical carcinogenesis, the dorsal skin of NQO1-deficient (NQO1-/-) and wild-type (NQO1+/+) mice were treated with a single dose of benzo(a)pyrene, followed by twice weekly applications of phorbol-12-myristate-13-acetate. The NQO1-/- mice showed a much higher frequency of skin tumor development when compared with their wild-type littermates. Interestingly, the male NQO1-/- mice were slower to develop skin tumors than their NQO1-/- female littermates. Histological analysis of the NQO1-/- tumors showed proliferative activity. These results demonstrate that NQO1 acts as an endogenous factor in protection against benzo(a)pyrene carcinogenicity.
Long
D J
DJ
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030, USA.
Waikel
R L
RL
Wang
X J
XJ
Perlaky
L
L
Roop
D R
DR
Jaiswal
A K
AK
D000818:Animals; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics / Q000633:toxicity*; D001711:Biotransformation; D002273:Carcinogens / Q000493:pharmacokinetics / Q000633:toxicity*; D003043:Cocarcinogenesis; D004198:Disease Susceptibility; D005260:Female; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D023421:Models, Animal; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000201:enzymology; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology*; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity
D002273:Carcinogens; D001564:Benzo(a)pyrene; D016660:NAD(P)H Dehydrogenase (Quinone); D013755:Tetradecanoylphorbol Acetate