Prevention of bromobenzene toxicity by N-acetylmethionine: correlation between toxicity and the impairment in O- and S-methylation of bromothiocatechols.
Bromobenzene (800 mg/kg, ip) caused severe liver necrosis with massive hemorrhage in the golden Syrian hamster within the first 24 hr. Kidney injury was also observed. Treatment with N-acetylmethionine (NAM) at an ip dose of 1200 mg/kg at 5 hr after bromobenzene administration significantly protected the liver and kidney against injuries. Plasma glutamate pyruvate transaminase and blood urea nitrogen levels were substantially decreased in the NAM-treated animals. Histological evaluations confirmed these results. When the urinary neutral and phenolic metabolites of bromobenzene from NAM-treated and untreated hamsters were isolated and compared by GC and GC/MS, a striking result was observed in terms of O- and S-methylated thiol-containing metabolite formation. The NAM-treated animals showed approximately a 8- to 14-fold increase in the excretion of the four isomeric O- and S-methylated bromothiocatechols. These thiocatechols, which are now known to be the 3,4-series metabolites of bromobenzene, can undergo methylation at either the thiol or the hydroxyl functional group. The excretion of 3-S- and 4-S-methylated bromodihydrobenzene thiolols was also increased significantly in the NAM-treated hamster, but other neutral and phenolic metabolites were relatively unchanged. These results suggest that bromobenzene toxicity in the Syrian hamster may be associated with impaired methylation capabilities, an impairment that could be due to methionine and glutathione depletion.
Lertratanangkoon
K
K
Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston 77555-1031.
Scimeca
J M
JM
D000818:Animals; D001969:Bromobenzenes / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000633:toxicity; D002396:Catechols / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury; D006224:Cricetinae; D007674:Kidney Diseases / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D008107:Liver Diseases / Q000473:pathology / Q000517:prevention & control; D008297:Male; D008647:Mesocricetus; D008715:Methionine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008745:Methylation; D009336:Necrosis / Q000139:chemically induced / Q000517:prevention & control; D013045:Species Specificity; D013438:Sulfhydryl Compounds / Q000378:metabolism
D001969:Bromobenzenes; D002396:Catechols; D013438:Sulfhydryl Compounds; C006379:N-acetylmethionine; D008715:Methionine; C032036:bromobenzene