Toxicity of nitrobenzene compounds towards isolated hepatocytes: dependence on reduction potential.
1. The cytotoxicity of p-substituted nitrobenzenes towards isolated hepatocytes under aerobic or hypoxic conditions has been determined. The nitrobenzene concentration required to cause 50% cytoxicity in 2 h was a function of the one-electron reduction potential of the nitrobenzene, with the more cytotoxic compounds having the strongest electron-withdrawing substituents. 2. The effectiveness of the nitrobenzenes at causing cytotoxicity under aerobic but not hypoxic conditions was markedly increased if hepatocyte catalase was inhibited with azide. 3. Nitrobenzenes at cytotoxic concentrations induced cyanide-resistant respiration in isolated hepatocytes. Their effectiveness correlated with their cytotoxicity. 4. The rate of oxygen activation of these nitrobenzenes by ascorbate was also a function of the one-electron reduction potential. The nitro compounds with the strongest electron-withdrawing substituents were the most rapidly reduced. 5. Most nitrobenzenes were more cytotoxic under aerobic than hypoxic conditions. Ascorbate enhanced hypoxic, but not aerobic, cytotoxicity. 6. It was concluded that the cytotoxicity of different nitrobenzenes is related to their ease of reduction to nitro radical anions and nitrosobenzenes. Aerobic cytotoxicity is probably initiated by redox cycling and oxygen activation by the nitro radical anions whereas hypoxic cytotoxicity is probably initiated by the alkylation of macromolecules by nitrosobenzene metabolites.
O'Brien
P J
PJ
Faculty of Pharmacy, University of Toronto, Ontario, Canada.
Wong
W C
WC
Silva
J
J
Khan
S
S
D000478:Alkylation; D000818:Animals; D001205:Ascorbic Acid / Q000494:pharmacology; D001386:Azides / Q000494:pharmacology; D002374:Catalase / Q000037:antagonists & inhibitors; D015687:Cell Hypoxia / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects*; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007700:Kinetics; D008099:Liver / Q000166:cytology*; D008297:Male; D009578:Nitrobenzenes / Q000633:toxicity*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains
D001386:Azides; D009578:Nitrobenzenes; D002374:Catalase; D005978:Glutathione; D001205:Ascorbic Acid