In vivo Role of NAD(P)H:Quinone Oxidoreductase 1 in Metabolic Activation of Mitomycin C and Bone Marrow Cytotoxicity

Abstract

), and wild-type (WT) mice were exposed to five once weekly doses of mitomycin C. The mice were euthanized 15 weeks after the first dose. Blood cell counts and histologic analyses were done. WT and NQO2À/À mice showed hypocellularity and a significant increase in adipocytes in bone marrow. They also showed anemia because of the loss of RBC and hemoglobin. The neutrophils and platelets were reduced, whereas other blood cell types and tissues were normal. Interestingly, NQO1 À/À mice showed a complete resistance to mitomycin C-induced bone marrow cytotoxicity and reduction in RBC, hemoglobin, and neutrophils. NQO1 +/À mice also showed limited resistance to mitomycin C-induced bone marrow cytotoxicity. These data show a major in vivo role of NQO1 in metabolic activation of mitomycin C with implications in mitomycin C chemotherapy. [Cancer Res 2007;67(17):7966-71]

Genetic evidence for NAD(P)H:quinone oxidoreductase 1-catalyzed quinone reduction on passage through the mouse pulmonary circulation

“…CoQ 1 was selected for comparison with DQ, because both were reduced on passage through the rat lung, wherein NQO1 was implicated as the dominant reductase for DQ and a contributing reductase for CoQ 1 . Their reactivity with NQO1 in the rat lung was not that surprising, since DQ and CoQ 1 have nearly the same water and lipid solubility properties and can act as common electron acceptors for NQO1 as the isolated enzyme or within cells (11,14,16,20).…”

“…The preference for DQ over CoQ 1 as an NQO1 electron acceptor is suggested by structure-activity studies showing that quinones with van der Waals volumes of Ͻ200 Å (162.9 Å for DQ and 243.96 Å for CoQ 1 ) have been observed to act as relatively "fast" NQO1 substrates (high K cat /K m ) (3,28,41). In any case, the differential impact of intact mouse and rat lung NQO1 on CoQ 1 illustrates the concept that quinone fate in the lung depends on the properties of the substances themselves (e.g., propensity to act as an electron acceptor for any given reductase), as well as the properties of the pulmonary endothelium and lung tissue (e.g., relative activities and complement of available redox enzymes). Accordingly, for a range of redox compounds we have studied, including DQ, CoQ 1 , coenzyme Q 0 , and the thiazine polymer (toluidine blue O-polyacrylamide polymer), their different physical and chemical properties influence the subcellular reduction sites, the electron donor utilized, and the dominant reductase(s) involved (4 -8, 12, 29, 31).…”

“…The present study demonstrates that DQ acts as a probe of lung tissue NQO1 activity on passage through the pulmonary circulation. The need for such a probe is exemplified by the complexity and diversity of roles for NQO1 and polymorphisms resulting in inactive forms of the enzyme in pharmacology, toxicology, and pathophysiology (1,17,22,42). More detailed studies of lung DQ redox metabolism are likely to provide information regarding the therapeutic potential for lung NQO1-targeted activation of anticancer drugs and antioxidants, as well as a better understanding of lung toxicity of various redox-active xenobiotics.…”

“…These observations emphasize the importance of using intact organs in metabolism studies and suggest the intriguing possibility that DQ acts as a specific NQO1 activity probe in the perfused lung. Since there are no means to assess NQO1 activity in vivo, confirmation that DQ can be used for this purpose would represent an advance in studies of NQO1 as a target of drug activation and xenobiotic detoxification and as a factor in susceptibility to oxidative stress, various malignancies, and other pathophysiological conditions in the lung and other organs (1, 10, 11, 14, 15, 21-23, 25, 26, 33, 34, 38, 39, 43-45).The Nqo1-null (NQO1 Ϫ/Ϫ ) mouse has been used extensively to evaluate the contribution of metabolic and nonmetabolic functions of the enzyme, e.g., in susceptibility to carcinogenic and chemotherapeutic compounds and environmental toxins, tissue redox imbalance, and various disease processes (1,2,10,21,23,26,33,43,44). Nevertheless, there have been few studies of quinone metabolism in NQO1 Ϫ/Ϫ mouse tissues and none in intact organs (24).…”

“…The Nqo1-null (NQO1 Ϫ/Ϫ ) mouse has been used extensively to evaluate the contribution of metabolic and nonmetabolic functions of the enzyme, e.g., in susceptibility to carcinogenic and chemotherapeutic compounds and environmental toxins, tissue redox imbalance, and various disease processes (1,2,10,21,23,26,33,43,44). Nevertheless, there have been few studies of quinone metabolism in NQO1 Ϫ/Ϫ mouse tissues and none in intact organs (24).…”