In-vitro mechanisms of 1,2-dichloropropane nephrotoxicity using the renal cortical slice model.
1. Renal cortical slices isolated from the kidneys of male Wistar rats were used as an experimental model for studying the nephrotoxicity induced by 1,2-dichloropropane. 2. The solvent causes a depletion of renal reduced glutathione content and slight, but significant, lipid peroxidation. The block of the oxidative pathway with carbon monoxide prevents glutathione content depletion, and shows that this conjugation is the major step in 1,2-dichloropropane metabolism. 3. Loss of organic anion accumulation and release into the incubation medium of tubular enzymes, mainly from the soluble fraction, are the toxic effects of the solvent. The brush border is only slightly affected. 4. The mechanism of nephrotoxicity appears to occur via mercapturic acid metabolism. Acivicin and aminooxyacetic acid, inhibitors of gamma-glutamyltransferase and beta-lyase activity, respectively, partially but significantly prevent the loss of organic anion accumulation induced by 1,2-dichloropropane. Furthermore, alpha-ketobutyrate, an activator of beta-lyase, enhances the effects of 1,2-dichloropropane on the target, but is itself toxic for organic anion accumulation.
Trevisan
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Istituto di Medicina del Lavoro, Laboratorio di Tossicologia Industriale, Università di Padova, Italy.
Meneghetti
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Maso
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Troso
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D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D007674:Kidney Diseases / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000097:blood; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D011407:Propane / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D005723:gamma-Glutamyltransferase / Q000097:blood
D002248:Carbon Monoxide; D007770:L-Lactate Dehydrogenase; D005723:gamma-Glutamyltransferase; D000410:Alanine Transaminase; D005978:Glutathione; C004765:propylene dichloride; D011407:Propane