Article

ChemInform Abstract: NAD(P)H:quinone Oxidoreductase 1 (NQO1): Chemoprotection, Bioactivation, Gene Regulation and Genetic Polymorphisms

Department of Pharmaceutical Sciences, School of Pharmacy and Cancer Center, Box C-238, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Denver, CO 80262, USA.
Chemico-Biological Interactions (Impact Factor: 2.58). 05/2001; 129(1-2):77-97. DOI: 10.1016/S0009-2797(00)00199-X
Source: PubMed

ABSTRACT

NAD(P)H:quinone oxidoreductase 1 (NQO1) is an obligate two-electron reductase that is involved in chemoprotection and can also bioactivate certain antitumor quinones. This review focuses on detoxification reactions catalyzed by NQO1 and its role in antioxidant defense via the generation of antioxidant forms of ubiquinone and vitamin E. Bioactivation reactions catalyzed by NQO1 are also summarized and the development of new antitumor agents for the therapy of solid tumors with marked NQO1 content is reviewed. NQO1 gene regulation and the role of the antioxidant response element and the xenobiotic response element in transcriptional regulation is summarized. An overview of genetic polymorphisms in NQO1 is presented and biological significance for chemoprotection, cancer susceptibility and antitumor drug action is discussed.

Download full-text

Full-text

Available from: Howard D Beall
  • Source
    • "PARP-1 activation is also known as one of the important pathogenic mechanisms in cisplatin-induced toxicity (Mukhopadhyay et al., 2011; Shino et al., 2003). The cytosolic antioxidant flavoprotein NADH:quinone oxidoreductase 1 (NQO1) uses NADH as an electron donor to catalyze the reduction of substrates, which consequently increases intracellular NAD þ levels (Gaikwad et al., 2001; Ross et al., 2000). NQO1 has also been implicated in anti-inflammatory processes, scavenging of superoxide anion radicals, and stabilization of p53 and other tumor suppressor proteins (Jones et al., 2007; Moscovitz et al., 2012; Pazdro and Burgess, 2012). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ototoxicity is an important issue in patients receiving cisplatin chemotherapy. Numerous studies have demonstrated that cisplatin-induced ototoxicity is related to oxidative stress and DNA damage. However, the precise mechanism underlying cisplatin-associated ototoxicity is still unclear. The cofactor nicotinamide adenine dinucleotide (NAD(+)) has emerged as an important regulator of energy metabolism and cellular homeostasis. Here, we demonstrate that the levels and activities of sirtuin-1 (SIRT1) are suppressed by the reduction of intracellular NAD(+) levels in cisplatin-mediated ototoxicity. We provide evidence that the decreases in SIRT1 activity and expression facilitated by increasing poly(ADP-ribose) polymerase-1 (PARP-1) activation and microRNA-34a levels through cisplatin-mediated p53 activation aggravate the associated ototoxicity. Furthermore, we show that the induction of cellular NAD(+) levels using dunnione, which targets intracellular NQO1, prevents the toxic effects of cisplatin through the regulation of PARP-1 and SIRT1 activity. These results suggest that direct modulation of cellular NAD(+) levels by pharmacological agents could be a promising therapeutic approach for protection from cisplatin-induced ototoxicity. Copyright © 2015 Elsevier B.V. All rights reserved.
    Full-text · Article · Sep 2015 · Hearing research
  • Source
    • "The enzyme catalyses the NADH or NADPH-dependent reduction of a variety of organic compounds, including quinones [78] [79] [80] [81] [82]. Its cellular role is not wholly clear, but it seems likely that NQO1 participates in the detoxification of xenobiotic compounds and also in the cycling of quinones in the cell [75]. Since it catalyses the two electron reduction of quinones directly to the corresponding quinols, it avoids the production of potentially damaging semiquinones [83]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Dicoumarol, a symmetrical biscoumarin can be considered as the "parent" of the widely used anticoagulant drug, warfarin. The discovery of dicoumarol's bioactive properties resulted from an investigation into a mysterious cattle disease in the 1940s. It was then developed as a pharmaceutical, but was superseded in the 1950s by warfarin. Both dicoumarol and warfarin antagonise the blood clotting process through inhibition of vitamin K epoxide reductase (VKOR). This blocks the recycling of vitamin K and prevents the γ-carboxylation of glutamate residues in clotting factors. VKOR is an integral membrane protein and our understanding of the molecular mechanism of action of dicoumarol and warfarin is hampered by the lack of a three dimensional structure. There is consequent controversy about the membrane topology of VKOR, the location of the binding site for coumarin inhibitors and the mechanism of inhibition by these compounds. Dicoumarol (and warfarin) also inhibit a second enzyme, NAD(P)H quinone oxidoreductase 1 (NQO1). This soluble, cytoplasmic enzyme may also play a minor role in the recycling of vitamin K. However, its main cellular roles as an enzyme appear to be detoxification and the prevention of the build-up of reactive oxygen species. NQO1 is well characterised biochemically and structurally. Consequently, structure-based drug design has identified NQO1 inhibitors which have potential for the development of anti-cancer drugs. Many of these compounds are structurally related to dicoumarol and some have reduced "off target" effects. Therefore, it is possible that dicoumarol will become the "parent" of a second group of drugs.
    Full-text · Article · Jul 2015 · Current drug targets
  • Source
    • "17-DMAG also demonstrated significant toxicities in phase I clinical trials, including hepatotoxicity as reflected by changes in liver function (Pacey et al., 2011). The toxicity of quinones, such as BQAs, arises from their ability to redox cycle and/or arylate cellular nucleophiles (Ross et al., 2000). These molecules are capable of both redox cycling to produce reactive oxygen species and reaction with thiols at the 19-substituent, leading to the formation of glutathione conjugates and adducts with cellular proteins (Guo et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Unlabelled: The benzoquinone ansamycins (BQAs) are a valuable class of antitumor agents that serve as inhibitors of heat shock protein (Hsp)-90. However, clinical use of BQAs has resulted in off-target toxicities, including concerns of hepatotoxicity. Mechanisms underlying the toxicity of quinones include their ability to redox cycle and/or arylate cellular nucleophiles. We have therefore designed 19-substituted BQAs to prevent glutathione conjugation and nonspecific interactions with protein thiols to minimize off-target effects and reduce hepatotoxicity. 19-Phenyl- and 19-methyl-substituted versions of geldanamycin and its derivatives, 17-allylamino-17-demethoxygeldanamycin and 17-(dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG), did not react with glutathione, whereas marked reactivity was observed using parent BQAs. Importantly, although 17-DMAG induced cell death in primary and cultured mouse hepatocytes, 19-phenyl and 19-methyl DMAG showed reduced toxicity, validating the overall approach. Furthermore, our data suggest that arylation reactions, rather than redox cycling, are a major mechanism contributing to BQA hepatotoxicity. 19-Phenyl BQAs inhibited purified Hsp90 in a Nad(p)h: quinone oxidoreductase 1 (NQO1)-dependent manner, demonstrating increased efficacy of the hydroquinone ansamycin relative to its parent quinone. Molecular modeling supported increased stability of the hydroquinone form of 19-phenyl-DMAG in the active site of human Hsp90. In human breast cancer cells, 19-phenyl BQAs induced growth inhibition also dependent upon metabolism via NQO1 with decreased expression of client proteins and compensatory induction of Hsp70. These data demonstrate that 19-substituted BQAs are unreactive with thiols, display reduced hepatotoxicity, and retain Hsp90 and growth-inhibitory activity in human breast cancer cells, although with diminished potency relative to parent BQAs.
    Preview · Article · Mar 2014 · Molecular pharmacology
Show more