Effects of 1,3-dichloropropene on the kidney of Fisher 344 rats after pretreatment with diethyl maleate, buthionine sulfoximine, and aminooxyacetic acid.
Acute nephrotoxicity of cis/trans-1,3-dichloropropene (DCP) was assessed in male Fisher 344 rats. Pretreatment of rats with corn oil, aminooxyacetic acid (AOA), buthionine sulfoximine (BSO), or diethyl maleate (DEM) was given intraperitoneally 1 h or 4 h prior to injection of DCP. Doses of DCP were 0, 25, 50, and 75 mg/kg intraperitoneally (4-5 animals per dose/pretreatment group). Urine was collected for 24 h. Excretion of creatinine, phosphorus, protein, N-acetylglucosaminidase (NAG), and the major metabolite of DCP, N-acetyl-S-(cis-3-chloroprop-2-enyl)-cysteine (3CNAC), was measured. Excretion of the metabolite, 3CNAC, increased in a dose-related manner from 0 to 50 mg/kg of DCP, but further increases were not seen at the 75 mg/kg dose. The pretreatments produced no alterations in the amounts of metabolite excreted when compared to corn oil controls. Zero-order metabolism or impaired metabolism is suggested to be occurring at high doses of DCP. The AOA pretreatment group showed no increase in the excretion of NAG, whereas other pretreatments (corn oil, BSO, DEM) showed elevations of NAG excretion at the highest DCP doses. AOA inhibits renal beta-lyase, an enzyme that mediates cleavage of mercapturic acid metabolites to toxic products. Since NAG excretion was not elevated in response to DCP with AOA pretreatment and was not raised by pretreatments that deplete glutathione, it is suggested that nephrotoxic effects of DCP may be mediated through the mercapturic acid metabolites on the kidney, rather than due to glutathione depletion per se.
Osterloh
J
J
Department of Laboratory Medicine, University of California, San Francisco.
He
X W
XW
D000085:Acetates / Q000494:pharmacology*; D000118:Acetylglucosaminidase / Q000378:metabolism; D000498:Allyl Compounds / Q000378:metabolism / Q000633:toxicity*; D000625:Aminooxyacetic Acid / Q000494:pharmacology*; D000818:Animals; D000969:Antinematodal Agents / Q000633:toxicity*; D019328:Buthionine Sulfoximine; D004305:Dose-Response Relationship, Drug; D006843:Hydrocarbons, Chlorinated; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000494:pharmacology*; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010758:Phosphorus / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344
D000085:Acetates; D000498:Allyl Compounds; D000969:Antinematodal Agents; D006843:Hydrocarbons, Chlorinated; D008298:Maleates; D011506:Proteins; D000625:Aminooxyacetic Acid; D008717:Methionine Sulfoximine; D010758:Phosphorus; D019328:Buthionine Sulfoximine; C023891:1,3-dichloro-1-propene; D000118:Acetylglucosaminidase; C014476:diethyl maleate