Is the nephrotoxicity of (R)-3-chlorolactate in the rat caused by 3-chloropyruvate?
1. When (R, S)-[3-36 Cl]chlorolactate was administered to male rats, two radioactive constituents were excreted in the urine. These were identified as 36Cl- and [3-36 Cl]chlorolactate which was subsequently shown to be essentially the (S)-isomer. 2. Analysis of the urinary oxalate content from rats receiving either (R)- or (S)-3-chlorolactate revealed that elevated levels were produced by the (R)-isomer whereas normal levels followed the administration of the (S)-isomer. 3. Treatment of (R,S)-3-chlorolactate with a modified Fenton's oxidizing system produced oxalate and an intermediate which was identified as 3-chloropyruvate. 4. 3-Chloropyruvate is a potent nephrotoxin in the rat producing a brief phase of diuresis when administered, increasing the urinary excretion of oxalate and inhibiting the oxidative metabolic capability of rat kidney tubules and rat kidney mitochondria in vitro. 5. Both (R)-3-chlorolactate and 3-chloropyruvate were shown to be inhibitors of the commercially-available pyruvate dehydrogenase complex. 6. 3-Chloropyruvate inhibits kidney mitochondrial metabolism possibly at the pyruvate dehydrogenase complex level and appears to be a metabolite of (R)- but not (S)-3-chlorolactate.
Dobbie
M S
MS
Department of Biochemistry, University of Sydney, N.S.W., Australia.
Porter
K E
KE
Jones
A R
AR
D000818:Animals; D001711:Biotransformation; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D007773:Lactates / Q000633:toxicity*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism
D007773:Lactates; D011768:Pyruvate Dehydrogenase Complex; C007000:3-chlorolactate