Trichloroethylene induced vitamin B(12) and folate deficiency leads to increased formic acid excretion in the rat.
Exposure of rats to trichloroethylene induces a sustained excretion of large amounts of formic acid in urine. Both of the major metabolites, trichloroethanol and trichloroacetic acid, were found to induce this response, but not the minor metabolite S-(1, 2-dichlorovinyl) cysteine. Other polychlorinated solvents, including carbon tetrachloride and chloroform, also increased urinary formate excretion. Addition of folic acid either to diet or drinking water modulated the response indicating that these rats were folate deficient. Two markers of vitamin B(12) deficiency, methylmalonic acid and 5-methyltetrahydrofolate, were also markedly increased in urine and plasma respectively. The increase in 5-methyltetrahydrofolate is consistent with a folate deficiency caused by an inhibition of the vitamin B(12) dependent methionine salvage pathway. Since both vitamin B(12) and chemicals containing polychlorinated carbon atoms readily form free radicals, it is suggested that trichloroacetic acid and trichloroethanol interact with vitamin B(12) through a free radical mechanism inducing a B(12) deficiency and, as a consequence, a folate deficiency. As a result of the folate deficiency, excess formic acid, which is normally utilised through this pathway, is excreted in urine.
Dow
J L
JL
Zeneca, Central Toxicology Laboratory, Alderley Park, Macclesfield, Cheshire, UK.
Green
T
T
D018685:Anesthetics, Inhalation / Q000493:pharmacokinetics / Q000633:toxicity*; D000818:Animals; D001419:Bacteria / Q000187:drug effects / Q000378:metabolism; D001711:Biotransformation; D002374:Catalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000139:chemically induced*; D005561:Formates / Q000652:urine*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D012997:Solvents / Q000493:pharmacokinetics / Q000633:toxicity*; D014241:Trichloroethylene / Q000493:pharmacokinetics / Q000633:toxicity*; D014806:Vitamin B 12 Deficiency / Q000139:chemically induced*
D018685:Anesthetics, Inhalation; D005561:Formates; D012997:Solvents; C030544:formic acid; D014241:Trichloroethylene; D002374:Catalase