title: NRH:quinone oxidoreductase 2 (NQO2) catalyzes metabolic activation of quinones and anti-tumor drugs.
abstract: NRH:quinone oxidoreductase 2 (NQO2) is a cytosolic flavoprotein that utilizes NRH as electron donor. The present studies investigate the role of NQO2 in metabolic detoxification/activation of quinones and quinone based anti-tumor drugs. Chinese hamster ovary (CHO) cells stably overexpressing cDNA derived mouse NQO2 and mouse keratinocytes from DMBA-induced skin tumors in wild-type and NQO2-null mice were generated. The CHO cells overexpressing NQO2 and mouse keratinocytes expressing or deficient in NQO2 were treated with varying concentrations of mitomycin C (MMC), CB1954, MMC analog BMY25067, EO9, menadione and BP-3,6-quinone, in the absence and presence of NRH. The cytotoxicity of the drugs was evaluated by colony formation. The CHO cells overexpressing higher levels of mouse NQO2 showed significantly increased cytotoxicity to menadione, BP-3,6-quinone and to the anti-tumor drugs MMC and CB1954 when compared to CHO cells expressing endogenous NQO2. The cytotoxicity increased in presence of NRH. Similar results were also observed with BMY25067 and EO9 treatments, but to a lesser extent. The results on keratinocytes deficient in NQO2 supported the data from CHO cells. The inclusion of NRH had no effect on cytotoxicity of quinones and drugs in keratinocytes deficient in NQO2. Mouse NQO2 protein was expressed in bacteria, purified and used to study the role of NQO2 in MMC-induced DNA cross-linking. Bacterially expressed and purified NQO2 efficiently catalyzed MMC activation that led to DNA cross-linking. These results concluded that NQO2 plays a significant role in the metabolic activation of both quinones and anti-tumor drugs leading to cytotoxicity and cell death.
authors.affiliation: Department of Pharmacology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Claudia M
authors.initials: CM
authors.lastname: Celli
authors.forename: Namphuong
authors.initials: N
authors.lastname: Tran
authors.forename: Richard
authors.initials: R
authors.lastname: Knox
authors.forename: Anil K
authors.initials: AK
authors.lastname: Jaiswal
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D001388:Aziridines / Q000378:metabolism / Q000494:pharmacology; D001580:Benzopyrenes / Q000378:metabolism / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects*; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D003432:Cross-Linking Reagents / Q000378:metabolism / Q000494:pharmacology; D018076:DNA, Complementary / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D006873:Hydroquinones / Q000378:metabolism / Q000494:pharmacology; D045563:Indolequinones / Q000378:metabolism / Q000494:pharmacology; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016685:Mitomycin / Q000378:metabolism / Q000494:pharmacology; D008937:Mitomycins / Q000378:metabolism / Q000494:pharmacology; D011808:Quinone Reductases / Q000235:genetics / Q000378:metabolism*; D011809:Quinones / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D024483:Vitamin K 3 / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001388:Aziridines; D001580:Benzopyrenes; D003432:Cross-Linking Reagents; D018076:DNA, Complementary; D006873:Hydroquinones; D045563:Indolequinones; D008937:Mitomycins; D011809:Quinones; D016685:Mitomycin; C054191:benzo(a)pyrene-3,6-quinol; D024483:Vitamin K 3; C100099:tretazicar; C055172:N-7-(2-(nitrophenyldithio)ethyl)mitomycin C; C419642:NRH - quinone oxidoreductase2; D011808:Quinone Reductases; C060817:apaziquone