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 gr anule cell layer of the rat cerebellum. As part of a study to understa nd the mechanism of selective toxicity we have investigated the metabo lism and disposition of [2-C-14]L-CPA in the rat, with particular emph asis on the brain. Following a single oral nontoxic dose of 250 mg/kg or a neurotoxic dose of 750 mg/kg or 250 mg/kg per day for 3 days, L-C PA is very rapidly absorbed from the gastrointestinal tract into the b lood 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 r eadily cleared from the plasma with a half-life of 2.6 h. The only met abolite detected in the plasma was 2-S-cysteinylpropanoic acid, presum ably 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 sma ller amount excreted as the mercapturate, 2-S-N-acetylcysteinylpropano ic acid. Little radiolabel from L-CPA is excreted in the faeces, howev er. similar to 18% of a 250 mg/kg dose of L-CPA is eliminated as carbo n dioxide. The radiolabel from [2-C-14]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 th e cerebellum. Whole body autoradiography studies indicated some select ive retention of radiolabel in the cerebellum after the third dose of 250 mg/kg [2-C-14]L-CPA. Our findings indicate that the initial insult to the cerebellum following L-CPA administration is probably due to t he parent compound however, the prolonged presence of 2-S-cysteinylpro panoic 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 selec tive neurotoxicity of L-CPA requires further study.