Activation of alpha(1)-adrenergic receptors potentiates the nephrotoxicity of ethylene dibromide.
Ethylene dibromide (EDB) has been used as a model compound for eliciting hepato- and nephrotoxicity. Conjugation with glutathione (GSH) has been shown to play a role in the bioactivation of EDB. The aim of this study was to determine whether activation of alpha(1)-adrenergic receptors, which causes a decrease in cellular GSH levels, could modulate the nephrotoxicity of EDB. For this purpose, male ICR mice were treated with EDB and/or the alpha-adrenergic agonist, phenylephrine (Pe), or the alpha-adrenergic antagonist, phentolamine (Phe). Animals treated with EDB (40 mg/kg, i.p.) had a 9.3-fold increase in urinary gamma-glutamyltranspeptidase (GGTP: EC 2.3.2.2) activity and a 38% decrease in renal non-protein bound sulfhydryl (NPSH) levels; however, animals co-treated with EDB and Pe (50 mg/kg, i.p.) exhibited a 27.8-fold increase in urinary GGTP activity and a 60% decrease in NPSH levels. The enhanced presence of urinary GGTP and decrease in cellular levels of NPSH was nearly blocked by treating animals concomitantly with EDB and Phe (10 mg/kg, i.p.) or EDB, Pe, and Phe. Histopathological examination revealed the enhanced degree of tissue damage and necrosis following treatment with EDB and Pe, and the protective effect of Phe at ameliorating EDB toxicity. These results indicate that factors that can influence alpha-adrenergic receptors may be critical in assessing dose-response data used in the risk assessment process.
Harbison
Raymond D
RD
Department of Environmental and Occupational Health, College of Public Health, University of South Florida, 13201 Bruce B Downs Boulevard, MDC 56, Tampa, FL 33612, USA. rharbiso@hsc.usf.edu
Stedeford
Todd
T
Muro-Cacho
Carlos
C
Mosquera
Diana I
DI
Banasik
Marek
M
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists / Q000633:toxicity*; D000317:Adrenergic alpha-Antagonists / Q000633:toxicity; D000818:Animals; D002395:Catecholamines / Q000097:blood; D004357:Drug Synergism; D015946:Ethylene Dibromide / Q000633:toxicity*; D007306:Insecticides / Q000633:toxicity*; D007668:Kidney / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010646:Phentolamine / Q000633:toxicity; D010656:Phenylephrine / Q000633:toxicity; D013438:Sulfhydryl Compounds / Q000378:metabolism; D005723:gamma-Glutamyltransferase / Q000652:urine
D058646:Adrenergic alpha-1 Receptor Agonists; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D002395:Catecholamines; D007306:Insecticides; D013438:Sulfhydryl Compounds; D015946:Ethylene Dibromide; D010656:Phenylephrine; D005723:gamma-Glutamyltransferase; D010646:Phentolamine