ArticleBritish journal of cancer1993
Molecular mechanisms of SR 4233-induced hepatocyte toxicity under aerobic versus hypoxic conditions.
Article in British journal of cancer, 1993. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed.
- Kinetics of Flavoenzyme-Catalyzed Reduction of Tirapazamine Derivatives: Implications for Their Prooxidant Cytotoxicity.International journal of molecular sciences · 2019Article
- Pre-clinical and clinical investigations of metabolic zonation in liver diseases: The potential of microphysiology systems.Experimental biology and medicine (Maywood, N.J.) · 2017Review
- Reductive Metabolism Influences the Toxicity and Pharmacokinetics of the Hypoxia-Targeted Benzotriazine Di-Oxide Anticancer Agent SN30000 in Mice.Frontiers in pharmacology · 2017Article
- Mechanisms of Antibacterial Action of Quinoxaline 1,4-di-Frontiers in microbiology · 2016Article
- Isotopic labeling experiments that elucidate the mechanism of DNA strand cleavage by the hypoxia-selective antitumor agent 1,2,4-benzotriazine 1,4-di-N-oxide.Chemical research in toxicology · 2014Article
- Zinc finger nuclease knock-out of NADPH:cytochrome P450 oxidoreductase (POR) in human tumor cell lines demonstrates that hypoxia-activated prodrugs differ in POR dependence.The Journal of biological chemistry · 2013Article
- Tirapazamine-induced DNA damage measured using the comet assay correlates with cytotoxicity towards hypoxic tumour cells in vitro.British journal of cancer · 1996Article
- Molecular mechanisms of tirapazamine (SR 4233, Win 59075)-induced hepatocyte toxicity under low oxygen concentrations.British journal of cancer · 1995Article
Corrections and comments
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Authors and funding
2 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
SR 4233 (3-amino-1,2,4-benzotriazine-1,4-dioxide) is the lead compound of the benzotriazene-di-N oxides which are selectively toxic to tumour cells under hypoxic conditions. However much higher concentrations given to rats caused bone marrow toxicity and necrosis of the low oxygen Zone 3 part of the liver. In the following effects of SR 4233 on hepatocytes under hypoxic vs aerobic conditions have been compared. (1) SR 4233 did not affect hepatocyte viability (as determined by plasma membrane disruption) or glutathione levels under aerobic conditions. SR 4233 however induced cyanide-resistant respiration, an indicator of redox cycling mediated oxidative stress and became cytotoxic if hepatocyte catalase or glutathione reductase was inactivated. Glutathione oxidation occurred well before cytotoxicity ensued. Addition of ascorbate markedly enhanced SR 4233 cytotoxicity to these compromised hepatocytes. (2) In contrast, SR 4233 was highly toxic to hypoxic hepatocytes. Addition of ascorbate to enhance SR 4233 reduction also caused a marked increase in hepatocyte toxicity and an SR 4233 radical was detected with ESR spectroscopy. SR 4233 cellular reduction and toxicity was prevented with fructose or inhibitors of NADPH:cytochrome P-450 reductase. Inactivation of catalase or glutathione reductase had no effect on SR 4233 toxicity and hepatocyte GSH was not oxidised indicating oxidative stress did not occur during hypoxic SR 4233 hepatocyte toxicity. (3) The lack of SR 4233 cytotoxicity under aerobic conditions could probably be attributed to the detoxification of the SR 4233 radical by mitochondrial oxidation as SR 4233, but not its metabolite SR 4317 markedly increased state III and IV mitochondrial respiration in the presence of NADH. The increased respiration was inhibited by the respiratory inhibitors KCN and antimycin A but not by rotenone. Furthermore SR 4233 cytotoxicity under aerobic conditions was markedly increased by partially inhibiting hepatocytes respiration with cyanide but not rotenone.
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