Protective effects of fomepizole on 2-chloroethanol toxicity.
2-Chloroethanol (2-CE) is a widely used industrial solvent. In Taiwan, Taiwanese farmers apply 2-CE on grape-vines to accelerate grape growth, a practice that in some cases have caused poisoning in humans. Thus, there is strong interest in identifying antidotes to 2-CE. This study examines the protective role in 2-CE intoxicated rats. Alcohol dehydrogenase and glutathione were hypothesized to be important in the metabolism of 2-CE. This study used fomepizole, an alcohol dehydrogenase inhibitor, and chemicals that affected glutathione metabolism to study 2-CE toxicity. Notably, fomepizole 5 mg/kg significantly increased median lethal dose (LD(50)) of 2-CE from 65.1 to 180 mg/kg and reduced the production of a potential toxic metabolite chloroacetaldehyde (CAA) in animal plasma. In contrast, disulfiram (DSF), an aldehyde dehydrogenase inhibitor, increased the toxicity of 2-CE on the lethality in rats. Additional or pretreatment with N-acetylcysteine (NAC) and fomepizole significantly reduced plasma CAA concentrations. Fomepizole also significantly reduced 2-CEinhibited glutathione activity. Otherwise, pretreatment with NAC for 4 days followed by co-treatment with fomepizole significantly decreased formation of the metabolic CAA. These results indicated that its catalytic enzyme might play a vital role during 2-CE intoxication, and the combination of fomepizole and NAC could be a protective role in cases of acute 2-CE intoxication.
Chen
Yng-Tay
YT
Department of Veterinary Medicine, National Chung-Hsing University, Taichung, Taiwan, Republic of China.
Liao
Jiunn-Wang
JW
Hung
Dong-Zong
DZ
D000079:Acetaldehyde / Q000031:analogs & derivatives / Q000097:blood; D000111:Acetylcysteine / Q000494:pharmacology / Q000627:therapeutic use; D000426:Alcohol Dehydrogenase / Q000037:antagonists & inhibitors*; D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors; D000818:Animals; D000931:Antidotes / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D004221:Disulfiram / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D005023:Ethylene Chlorohydrin / Q000378:metabolism / Q000633:toxicity*; D000077604:Fomepizole; D005978:Glutathione / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007928:Lethal Dose 50; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D011720:Pyrazoles / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000378:metabolism / Q000633:toxicity*
D000931:Antidotes; D000975:Antioxidants; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D012997:Solvents; D005023:Ethylene Chlorohydrin; D000077604:Fomepizole; C004656:chloroacetaldehyde; D000426:Alcohol Dehydrogenase; D000444:Aldehyde Dehydrogenase; D005978:Glutathione; D000079:Acetaldehyde; D004221:Disulfiram; D000111:Acetylcysteine