Disruption of the DT diaphorase (NQO1) gene in mice leads to increased menadione toxicity.
NAD(P)H:quinone oxidoreductase 1 (NQO1) is a flavoenzyme that catalyzes two-electron reductive metabolism and detoxification of quinones and their derivatives leading to protection of cells against redox cycling and oxidative stress. To examine the in vivo role of NQO1, a NQO1-null mouse was produced using targeted gene disruption. Mice lacking NQO1 gene expression showed no detectable phenotype and were indistinguishable from wild-type mice. However, NQO1-null mice exhibited increased toxicity when administered menadione compared with wild-type mice. These results establish a role for NQO1 in protection against quinone toxicity. The NQO1-null mice are a model for NQO1 deficiency in humans and can be used to determine the role of this enzyme in sensitivity to toxicity and carcinogenesis.
Radjendirane
V
V
Department of Pharmacology, Baylor College of Medicine, Houston, Texas 77030-3498, USA.
Joseph
P
P
Lee
Y H
YH
Kimura
S
S
Klein-Szanto
A J
AJ
Gonzalez
F J
FJ
Jaiswal
A K
AK
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002874:Chromosome Mapping; D004247:DNA / Q000737:chemistry / Q000302:isolation & purification; D008099:Liver / Q000201:enzymology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000235:genetics*; D010641:Phenotype; D051381:Rats; D011995:Recombination, Genetic; D014812:Vitamin K / Q000633:toxicity*
D014812:Vitamin K; D004247:DNA; D016660:NAD(P)H Dehydrogenase (Quinone); D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase