Interactions between bromobenzene dose, glutathione concentrations, and organ toxicities in single- and multiple-treatment studies.
A single oral dose of 4.0 mmol/kg bromobenzene transiently depleted hepatic and renal reduced nonprotein sulfhydryl group (NPS) concentrations, caused hepatocellular necrosis, and increased serum glutamic-pyruvic transaminase activity in male Fischer 344 rats. The depletion of NPS had partially reversed by 24 hr, and NPS concentrations were approximately twice normal values by 48 hr post-treatment. When the effects of single and repeated (once daily for 2, 4, or 10 days) treatments with 4.0 mmol/kg were compared, it was apparent that the severity of hepatotoxicity lessened and the percentage depletions of hepatic and renal NPS concentrations decreased with increasing length of bromobenzene treatment. There were essentially no signs of toxicity following the tenth treatment with 4.0 mmol/kg. Single-treatment studies indicated the following dose-response: 2.0 mmol/kg bromobenzene depleted liver NPS and was hepatotoxic, 0.5 mmol/kg caused a lesser depletion of liver NPS and was not (overtly) hepatotoxic, and 0.0625 mmol/kg was the maximum dose that did not deplete liver NPS. The responses to single and multiple (ten) treatments with these representative doses were compared. Liver injury was observed after a single but not after the tenth daily treatment with 2.0 mmol/kg. Both the single and the tenth administrations of 2.0 mmol/kg depleted hepatic NPS, but the percentage of depletion was greater after the first than after the tenth dose. Liver injury was not detected with lower dose regimens. The patterns of NPS depletion in liver and kidney were similar after single or multiple (ten) treatments. The minimum NPS concentrations produced, however, were lower after single than after multiple treatments. The molar amounts of liver NPS depleted after the tenth treatment appeared to be equivalent to or greater than those after the first, but prior bromobenzene exposure resulted in a higher concentration of tissue NPS being present at the time of the final treatment. Thus, the minimum tissue concentrations of NPS were greater after multiple treatments than after single treatments, despite the loss of equivalent amounts of NPS. It is concluded from these studies that repeated treatment produces resistance to bromobenzene hepatotoxicity. This protective adaptation may be due to a chemically induced increase in liver glutathione concentration.
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D001969:Bromobenzenes / Q000633:toxicity*; D002940:Circadian Rhythm / Q000187:drug effects; D003404:Creatinine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism*; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008297:Male; D009336:Necrosis; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D011916:Rats, Inbred F344; D013438:Sulfhydryl Compounds / Q000378:metabolism; D013997:Time Factors
D001969:Bromobenzenes; D013438:Sulfhydryl Compounds; D003404:Creatinine; C032036:bromobenzene; D005978:Glutathione