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Originally published In Press as doi:10.1074/jbc.M208675200 on September 25, 2002

J. Biol. Chem., Vol. 277, Issue 48, 46131-46139, November 29, 2002
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Disruption of Dihydronicotinamide Riboside:Quinone Oxidoreductase 2 (NQO2) Leads to Myeloid Hyperplasia of Bone Marrow and Decreased Sensitivity to Menadione Toxicity*

Delwin J. Long IIDagger §, Karim IskanderDagger §, Amos GaikwadDagger ||, Meral Arin**, Dennis R. Roop**, Richard KnoxDagger Dagger , Roberto Barrios§§, and Anil K. JaiswalDagger ¶¶

From the Departments of Dagger  Pharmacology, ** Molecular and Cellular Biology, and §§ Pathology, Baylor College of Medicine, Houston, Texas 77030 and the Dagger Dagger  Enact Pharma PLC, Building 115, Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, United Kingdom

Dihydronicotinamide riboside (NRH):quinone oxidoreductase 2 (NQO2) is a flavoenzyme that catalyzes the reductive metabolism of quinones. To examine the in vivo role of NQO2, NQO2-null (NQO2-/-) mice were generated using targeted gene disruption. Mice lacking NQO2 gene expression showed no detectable developmental abnormalities and were indistinguishable from wild-type (NQO2+/+) mice. However, NQO2-null mice exhibited myeloid hyperplasia of the bone marrow and increased neutrophils, basophils, eosinophils, and platelets in the peripheral blood. Decreased apoptosis of bone marrow cells and circulating granulocytes contributed to myeloid hyperplasia and hyperactivity of bone marrow in NQO2-null mice. The hematological changes in NQO2-/- mice were specifically associated with loss of the NQO2 gene because histological analysis of various tissues including spleen, thymus, blood cultures, and urine analysis demonstrated no sign of infection. NQO2-null mice also demonstrated decreased toxicity when exposed to menadione or menadione with NRH. These results establish a role for NQO2 in protection against myelogenous hyperplasia and in metabolic activation of menadione, leading to hepatic toxicity. The NQO2-null mice are a model for NQO2 deficiency in humans and can be used to determine the role of this enzyme in sensitivities to toxicity and carcinogenesis.

* This work was supported by National Institutes of Health Grant R01 ES07943.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Both authors contributed equally to this work.

Present address: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030.

|| Present address: Molecular Therapeutics, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030.

¶¶ To whom correspondence should be addressed: Dept. of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030. Tel.: 713-798-7691; Fax: 713-798-3145; E-mail: ajaiswal@bcm.tmc.edu.

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.


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