{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T14:25:01Z","timestamp":1780583101627,"version":"3.54.1"},"reference-count":55,"publisher":"MDPI AG","issue":"22","license":[{"start":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T00:00:00Z","timestamp":1605744000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000782","name":"European Science Foundation","doi-asserted-by":"publisher","award":["DOTSUT-34\/09.3.3.-LMT-K712-01-0058"],"award-info":[{"award-number":["DOTSUT-34\/09.3.3.-LMT-K712-01-0058"]}],"id":[{"id":"10.13039\/501100000782","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Derivatives of tirapazamine and other heteroaromatic N-oxides (ArN\u2192O) exhibit tumoricidal, antibacterial, and antiprotozoal activities, which are typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the role of NAD(P)H:quinone oxidoreductase (NQO1) in ArN\u2192O aerobic cytotoxicity. We synthesized 9 representatives of ArN\u2192O with uncharacterized redox properties and examined their single-electron reduction by rat NADPH:cytochrome P-450 reductase (P-450R) and Plasmodium falciparum ferredoxin:NADP+ oxidoreductase (PfFNR), and by rat NQO1. NQO1 catalyzed both redox cycling and the formation of stable reduction products of ArN\u2192O. The reactivity of ArN\u2192O in NQO1-catalyzed reactions did not correlate with the geometric average of their activity towards P-450R- and PfFNR, which was taken for the parameter of their redox cycling efficacy. The cytotoxicity of compounds in murine hepatoma MH22a cells was decreased by antioxidants and the inhibitor of NQO1, dicoumarol. The multiparameter regression analysis of the data of this and a previous study (DOI: 10.3390\/ijms20184602) shows that the cytotoxicity of ArN\u2192O (n = 18) in MH22a and human colon carcinoma HCT-116 cells increases with the geometric average of their reactivity towards P-450R and PfFNR, and with their reactivity towards NQO1. These data demonstrate that NQO1 is a potentially important target of action of heteroaromatic N-oxides.<\/jats:p>","DOI":"10.3390\/ijms21228754","type":"journal-article","created":{"date-parts":[[2020,11,19]],"date-time":"2020-11-19T10:46:26Z","timestamp":1605782786000},"page":"8754","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Aerobic Cytotoxicity of Aromatic N-Oxides: The Role of NAD(P)H:Quinone Oxidoreductase (NQO1)"],"prefix":"10.3390","volume":"21","author":[{"given":"Au\u0161ra","family":"Nemeikait\u0117-\u010c\u0117nien\u0117","sequence":"first","affiliation":[{"name":"State Research Institute Center for Innovative Medicine, Santari\u0161ki\u0173 St. 5, LT-08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4268-1716","authenticated-orcid":false,"given":"Jonas","family":"\u0160arlauskas","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lina","family":"Misevi\u010dien\u0117","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audron\u0117","family":"Marozien\u0117","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4614-3595","authenticated-orcid":false,"given":"Violeta","family":"Jonu\u0161ien\u0117","sequence":"additional","affiliation":[{"name":"Institute of Biosciences of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mindaugas","family":"Lesanavi\u010dius","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narimantas","family":"\u010c\u0117nas","sequence":"additional","affiliation":[{"name":"Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1042\/bss0610171","article-title":"Radicals from one-electron reduction of nitro compounds, aromatic N-oxides and quinones: The kinetic basis for hypoxia-selective, bioreductive drugs","volume":"61","author":"Wardman","year":"1995","journal-title":"Biochem. 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