Cellular toxicity of bromobenzene and bromobenzene metabolites to rabbit proximal tubules: the role and mechanism of 2-bromohydroquinone.
An in vitro model using a suspension of rabbit renal proximal tubules was developed to investigate the mechanism of nephrotoxicity of bromobenzene. Using oxygen consumption, glutathione concentrations and retention of lactate dehydrogenase activity as markers of toxicity, the rank order of potency was bromobenzene (5 mM) less than 2-bromophenol (2 mM) less than 3-, 4-bromophenol (1 mM) less than 2-bromohydroquinone (0.1 mM). These data support in vivo results and are consistent with the hypothesis that 2-bromohydroquinone or a metabolite thereof is responsible for bromobenzene-induced nephrotoxicity. Inhibitors of cytochrome P-450 and the cyclooxygenase and peroxidase components of prostaglandin H synthase did not protect the proximal tubules from 2-bromohydroquinone-induced toxicity, suggesting that these enzymes do not play a role in 2-bromohydroquinone bioactivation. There is a specific sequence of events in 2-bromohydroquinone-induced toxicity. Early events include decreased glutathione levels and inhibited mitochondrial respiration, whereas an increase in plasma membrane permeability is a late event.
D000818:Animals; D001711:Biotransformation; D001969:Bromobenzenes / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D005260:Female; D005978:Glutathione / Q000032:analysis; D006873:Hydroquinones / Q000378:metabolism / Q000633:toxicity*; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000187:drug effects* / Q000378:metabolism; D007770:L-Lactate Dehydrogenase / Q000032:analysis; D009761:Nystatin / Q000494:pharmacology; D010042:Ouabain / Q000494:pharmacology; D010101:Oxygen Consumption / Q000187:drug effects; D010636:Phenols / Q000633:toxicity; D011451:Prostaglandin-Endoperoxide Synthases / Q000502:physiology; D011817:Rabbits; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D013997:Time Factors
D001969:Bromobenzenes; D006873:Hydroquinones; D010636:Phenols; D009761:Nystatin; C042377:2-bromohydroquinone; D010042:Ouabain; D003577:Cytochrome P-450 Enzyme System; C032038:2-bromophenol; C032036:bromobenzene; D007770:L-Lactate Dehydrogenase; D011451:Prostaglandin-Endoperoxide Synthases; D000254:Sodium-Potassium-Exchanging ATPase; D005978:Glutathione; C032037:4-bromophenol; C040659:3-bromophenol; D007213:Indomethacin