title: Trichloroethylene-induced formic aciduria: effect of dose, sex and strain of rat.
abstract: The industrial solvent trichloroethylene (TCE) has been reported to increase the excretion of formic acid in the urine of male Fischer 344 (F-344) rats following large oral doses. We have examined the dose-response relationship for formic aciduria in male and female Fischer 344 rats, the effect of some known metabolites of TCE and examined the response in male Wistar rats to help understand its relevance to renal toxicity. We report that doses of TCE as low as 8 mg/kg for 3 days to both male and female F344 rats produced formic aciduria. The formic aciduria was time-dependent being more marked after 3 doses compared to one dose in male F344 rats and to a lesser extent in female F344 rats. TCE administration to male Wistar rats produced less formic aciduria than in male F344 rats, indicating a strain difference in response. As TCE is primarily metabolised by cytochrome P450 2E1, Wistar rats were administered inducers of cytochrome P450 2E1 followed by TCE, this increased formic acid excretion to a concentration similar to that observed in male F344 rats, indicating a role for P450. Administration of the major metabolites of TCE, trichloroethanol and trichloroacetic acid to male F344 rats also produced a marked and sustained formic aciduria, while the metabolite of TCE formed via glutathione conjugation had no effect on formic acid excretion. The mechanism whereby this response occurs is currently not understood, but the formic acid excreted is not a metabolite of TCE, but appears to be due to interference with the metabolic utilisation of formate by a down stream metabolite of TCE. Over the three days of the studies no histopathological evidence of kidney toxicity was observed in F344 rats given TCE, indicating that the perturbation of formate metabolism does not lead to acute renal injury.
authors.affiliation: School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Byrom Street, Liverpool, L3 3AF, UK.
authors.forename: Noreen
authors.initials: N
authors.lastname: Yaqoob
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Evans
authors.forename: Edward A
authors.initials: EA
authors.lastname: Lock
mesh_terms: D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004790:Enzyme Induction / Q000187:drug effects; D005023:Ethylene Chlorohydrin / Q000031:analogs & derivatives / Q000633:toxicity; D005260:Female; D005561:Formates / Q000652:urine*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D017208:Rats, Wistar; D012737:Sex Factors; D012997:Solvents / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D013045:Species Specificity; D013997:Time Factors; D014238:Trichloroacetic Acid / Q000633:toxicity; D014241:Trichloroethylene / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*
chemical_list: D005561:Formates; D012997:Solvents; C030544:formic acid; D014241:Trichloroethylene; D014238:Trichloroacetic Acid; D005023:Ethylene Chlorohydrin; C005849:2,2,2-trichloroethanol; D019392:Cytochrome P-450 CYP2E1