Lower induction of p53 and decreased apoptosis in NQO1-null mice lead to increased sensitivity to chemical-induced skin carcinogenesis.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a cytosolic protein that catalyzes metabolic detoxification of quinones and protects cells against redox cycling and oxidative stress. NQO1-null mice deficient in NQO1 protein showed increased sensitivity to 7,12-dimethylbenz(a)anthracene- and benzo(a)pyrene-induced skin carcinogenesis. In the present studies, we show that benzo(a)pyrene metabolite benzo(a)pyrene-trans-7,8-dihydrodiol-9,10-epoxide and not benzo(a)pyrene quinones contributed to increased benzo(a) pyrene-induced skin tumors in NQO1-null mice. An analysis of untreated skin revealed an altered intracellular redox state due to accumulation of NADH and reduced levels of NAD/NADH in NQO1-null mice as compared with wild-type mice. Treatment with benzo(a)pyrene failed to significantly increase p53 and apoptosis in the skin of NQO1-null mice when compared with wild-type mice. These results led to the conclusion that altered intracellular redox state along with lack of induction of p53 and decreased apoptosis plays a significant role in increased sensitivity of NQO1-null mice to benzo(a)pyrene-induced skin cancer.
Iskander
Karim
K
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030, USA.
Gaikwad
Amos
A
Paquet
Marilene
M
Long
Delwin J
DJ
Brayton
Cory
C
Barrios
Roberto
R
Jaiswal
Anil K
AK
D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide / Q000493:pharmacokinetics; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001564:Benzo(a)pyrene / Q000493:pharmacokinetics*; D002273:Carcinogens / Q000493:pharmacokinetics; D005260:Female; D008658:Inactivation, Metabolic; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000378:metabolism; D016660:NAD(P)H Dehydrogenase (Quinone); D009252:NADPH Dehydrogenase / Q000172:deficiency* / Q000378:metabolism; D010084:Oxidation-Reduction; D012867:Skin / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced* / Q000201:enzymology* / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53; D009243:NAD; D001564:Benzo(a)pyrene; D015123:7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D009252:NADPH Dehydrogenase; D013755:Tetradecanoylphorbol Acetate