The absence of cerebellar granule cell necrosis in the mouse following L-2-chloropropionic acid administration.
Oral administration of L-2-chloropropionic acid (L-CPA) to rats either as a single dose (750 mg/kg) or daily doses (250 mg/kg per day for 3 days) produces selective necrosis to the granule cell layer of the cerebellum. As part of a study to understand the mechanism of this selective toxicity, we investigated the toxicity of L-CPA and a related analogue, DL-2-bromopropionic acid to the mouse with particular emphasis on the brain. Following a single oral dose (up to 1000 mg/kg), or daily oral doses of 250 mg/kg per day L-CPA up to maximum tolerated doses, produced no evidence of neurotoxicity. Similarly, daily oral doses of DL-2-bromopropionic acid at 250 mg/kg per day produced no evidence of neurotoxicity. The basis for the lack of response was explored by examining the metabolism and disposition of L-[2-14C]-CPA in the mouse. Following a single oral dose of 250 mg/kg L-CPA, radioactivity was rapidly absorbed from the gastrointestinal tract into the blood stream. Peak plasma concentrations of radiolabel and L-CPA occurred within 2 h of dosing at about 1.8 mM, and were then lost from the plasma with a half-life of 1 h. The only metabolite detected in the plasma was 2-S-cysteinylpropanoic acid derived from the glutathione conjugate. About 39% of the dose was excreted in the urine in the first 24 h, mainly as 2-S-cysteinylpropanoic acid with only a small amount of unchanged L-CPA. The remaining radiolabel from L-CPA was excreted in the faeces (26%) and exhaled as carbon dioxide (about 14%) over 72 h. Radiolabel from L-[2-14C]-CPA was present in the cerebellum at a peak concentration of 1 mM 1-2 h after dosing and then was lost more slowly than from the plasma. Measurement of non-protein sulphydryl content in the brain, liver and kidneys showed a decrease in the liver and kidneys 4 h after dosing which recovered fairly rapidly, while a more prolonged decrease was found in the brain, especially the cerebellum. Our studies show that the mouse is refractory to cerebellar injury following treatment with L-CPA and DL-2-bromopropionic acid. The mouse appears to metabolize and excrete L-CPA as its glutathione-derived conjugate(s) more rapidly than the rat, thereby limiting the availability of L-CPA to the cerebellum, which may account for the absence of neuronal cell injury.
Lock
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Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK. ted.lock@ctl.zeneca.com
Gyte
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Duffell
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Wyatt
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D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000473:pathology*; D002851:Chromatography, High Pressure Liquid; D003594:Cytoplasmic Granules / Q000187:drug effects / Q000473:pathology*; D003600:Cytosol / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006207:Half-Life; D006843:Hydrocarbons, Chlorinated; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D009336:Necrosis; D011422:Propionates / Q000493:pharmacokinetics / Q000633:toxicity*; D014018:Tissue Distribution
D001786:Blood Glucose; D006843:Hydrocarbons, Chlorinated; D011422:Propionates; C021974:2-chloropropionic acid; D005978:Glutathione; C035775:2-bromopropionic acid