Protection of rats against 3-butene-1,2-diol-induced hepatotoxicity and hypoglycemia by N-acetyl-l-cysteine.
3-Butene-1,2-diol (BDD), an allylic alcohol and major metabolite of 1,3-butadiene, has previously been shown to cause hepatotoxicity and hypoglycemia in male Sprague-Dawley rats, but the mechanisms of toxicity were unclear. In this study, rats were administered BDD (250 mg/kg) or saline, ip, and serum insulin levels, hepatic lactate levels, and hepatic cellular and mitochondrial GSH, GSSG, ATP, and ADP levels were measured 1 or 4 h after treatment. The results show that serum insulin levels were not causing the hypoglycemia and that the hypoglycemia was not caused by an enhancement of the metabolism of pyruvate to lactate because hepatic lactate levels were either similar (1 h) or lower (4 h) than controls. However, both hepatic cellular and mitochondrial GSH and GSSG levels were severely depleted 1 and 4 h after treatment and the mitochondrial ATP/ADP ratio was also lowered 4 h after treatment relative to controls. Because these results suggested a role for hepatic cellular and mitochondrial GSH in BDD toxicity, additional rats were administered N-acetyl-l-cysteine (NAC; 200 mg/kg) 15 min after BDD administration. NAC treatment partially prevented depletion of hepatic cellular and mitochondrial GSH and preserved the mitochondrial ATP/ADP ratio. NAC also prevented the severe depletion of serum glucose concentration and the elevation of serum alanine aminotransferase activity after BDD treatment without affecting the plasma concentration of BDD. Thus, depletion of hepatic cellular and mitochondrial GSH followed by the decrease in the mitochondrial ATP/ADP ratio was likely contributing to the mechanisms of hepatotoxicity and hypoglycemia in the rat.
Sprague
Christopher L
CL
Department of Comparative Biosciences and Center for Molecular and Environmental Toxicology, University of Wisconsin School of Veterinary Medicine, 2015 Linden Drive, Madison, WI 53706, USA.
Elfarra
Adnan A
AA
D000098:Acetophenones / Q000737:chemistry; D000111:Acetylcysteine / Q000627:therapeutic use*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology / Q000517:prevention & control*; D002851:Chromatography, High Pressure Liquid; D016166:Free Radical Scavengers / Q000627:therapeutic use*; D005978:Glutathione / Q000378:metabolism; D006018:Glycols / Q000037:antagonists & inhibitors* / Q000097:blood / Q000633:toxicity*; D007003:Hypoglycemia / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D007328:Insulin / Q000097:blood; D007773:Lactates / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D000098:Acetophenones; D016166:Free Radical Scavengers; D006018:Glycols; D007328:Insulin; D007773:Lactates; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D005978:Glutathione; C006821:4-bromophenacyl bromide; C034598:3-butene-1,2-diol; D000111:Acetylcysteine