L-2-Chloropropionic acid metabolism and disposition in male rats: relevance to cerebellar injury.
L-2-Chloropropionic acid (L-CPA) produces selective necrosis to the granule cell layer of the rat cerebellum. As part of a study to understand the mechanism of selective toxicity we have investigated the metabolism and disposition of [2-14C]L-CPA in the rat, with particular emphasis on the brain. Following a single oral non-toxic dose of 250 mg/kg or a neurotoxic dose of 750 mg/kg or 250 mg/kg per day for 3 days, L-CPA is very rapidly absorbed from the gastrointestinal tract into the blood stream. Peak plasma concentrations of 2 mM (250 mg/kg) and 6 mM (750 mg/kg) L-CPA occurred within 1 h of dosing, and the compound was readily cleared from the plasma with a half-life of 2.6 h. The only metabolite detected in the plasma was 2-S-cysteinylpropanoic acid, presumably derived from the glutathione conjugate. About 60% of the dose is excreted in the urine in the first 24 h as unchanged L-CPA, with a smaller amount excreted as the mercapturate, 2-S-N-acetylcysteinylpropanoic acid. Little radiolabel from L-CPA is excreted in the faeces; however, approximately 18% of a 250 mg/kg dose of L-CPA is eliminated as carbon dioxide. The radiolabel from [2-14C]L-CPA present in the cerebellum, forebrain and liver at all time intervals examined was L-CPA. There was some indication of retention of L-CPA in the brain relative to the plasma with a small but consistently higher concentration found in the cerebellum. Whole body autoradiography studies indicated some selective retention of radiolabel in the cerebellum after the third dose of 250 mg/kg [2-14C]L-CPA. Our findings indicate that the initial insult to the cerebellum following L-CPA administration is probably due to the parent compound however, the prolonged presence of 2-S-cysteinylpropanoic acid in the plasma and concomitant depletion of glutathione in the cerebellum may also play a role in the toxicity. The relevance of the slightly greater retention of L-CPA in the cerebellum to the selective neurotoxicity of L-CPA requires further study.
Wyatt
I
I
Neurotoxicology Group, Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Farnworth
M
M
Gyte
A J
AJ
Lock
E A
EA
D000284:Administration, Oral; D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D002526:Cerebellar Diseases / Q000139:chemically induced*; D002851:Chromatography, High Pressure Liquid; D006843:Hydrocarbons, Chlorinated; D008297:Male; D011422:Propionates / Q000493:pharmacokinetics* / Q000633:toxicity*; D051381:Rats; D014018:Tissue Distribution
D006843:Hydrocarbons, Chlorinated; D011422:Propionates; C021974:2-chloropropionic acid