{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T18:49:45Z","timestamp":1785523785499,"version":"3.56.0"},"reference-count":53,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2019,9,17]],"date-time":"2019-09-17T00:00:00Z","timestamp":1568678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004895","name":"European Social Fund","doi-asserted-by":"publisher","award":["DOTSUT-34\/09.3.3-LMT-K-712-01-0058\/LSS-600000-58"],"award-info":[{"award-number":["DOTSUT-34\/09.3.3-LMT-K-712-01-0058\/LSS-600000-58"]}],"id":[{"id":"10.13039\/501100004895","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 promising antibacterial, antiprotozoal, and tumoricidal activities. Their action is typically attributed to bioreductive activation and free radical generation. In this work, we aimed to clarify the mechanism(s) of aerobic mammalian cell cytotoxicity of ArN\u2192O performing the parallel studies of their reactions with NADPH:cytochrome P-450 reductase (P-450R), adrenodoxin reductase\/adrenodoxin (ADR\/ADX), and NAD(P)H:quinone oxidoreductase (NQO1); we found that in P-450R and ADR\/ADX-catalyzed single-electron reduction, the reactivity of ArN\u2192O (n = 9) increased with their single-electron reduction midpoint potential (E17), and correlated with the reactivity of quinones. NQO1 reduced ArN\u2192O at low rates with concomitant superoxide production. The cytotoxicity of ArN\u2192O in murine hepatoma MH22a and human colon adenocarcinoma HCT-116 cells increased with their E17, being systematically higher than that of quinones. The cytotoxicity of both groups of compounds was prooxidant. Inhibitor of NQO1, dicoumarol, and inhibitors of cytochromes P-450 \u03b1-naphthoflavone, isoniazid and miconazole statistically significantly (p &lt; 0.02) decreased the toxicity of ArN\u2192O, and potentiated the cytotoxicity of quinones. One may conclude that in spite of similar enzymatic redox cycling rates, the cytotoxicity of ArN\u2192O is higher than that of quinones. This is partly attributed to ArN\u2192O activation by NQO1 and cytochromes P-450. A possible additional factor in the aerobic cytotoxicity of ArN\u2192O is their reductive activation in oxygen-poor cell compartments, leading to the formation of DNA-damaging species similar to those forming under hypoxia.<\/jats:p>","DOI":"10.3390\/ijms20184602","type":"journal-article","created":{"date-parts":[[2019,9,17]],"date-time":"2019-09-17T10:42:58Z","timestamp":1568716978000},"page":"4602","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity"],"prefix":"10.3390","volume":"20","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":"Department of Xenobiotics Biochemistry, 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":"Department of Biochemistry and Molecular Biology, Institute of Biosciences 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":"Department of Xenobiotics Biochemistry, 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":"Department of Xenobiotics Biochemistry, Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aliaksei V.","family":"Yantsevich","sequence":"additional","affiliation":[{"name":"Institute of Bioorganic Chemistry, NAS of Belarus, Kuprevicha 5\/2, BY-220072 Minsk, Belarus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narimantas","family":"\u010c\u0117nas","sequence":"additional","affiliation":[{"name":"Department of Xenobiotics Biochemistry, Institute of Biochemistry of Vilnius University, Saul\u0117tekio 7, LT-10257 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,17]]},"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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