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The effect of Trichloroethylene metabolites on the hepatic vitamin B12-dependent methionine-salvage pathway and its relevance to increased excretion of formic aciduria in the rat

Yaqoob, N, Bloch, KM, Evans, AR and Lock, E The effect of Trichloroethylene metabolites on the hepatic vitamin B12-dependent methionine-salvage pathway and its relevance to increased excretion of formic aciduria in the rat. Toxicological Research. ISSN 1976-8257 (Accepted)

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Abstract

The industrial solvent trichloroethylene (TCE) and its two major metabolites trichloroethanol (TCE-OH) and trichloroacetic acid (TCA) cause formic aciduria in male F344 rats. Prior treatment of male F344 rats with 1-aminobenzotriazole a cytochrome P450 inhibitor, followed by TCE (16mk/kg, po), completely prevented formic aciduria, but had no effect on formic acid excretion produced by TCA (8 or 16mg/kg, po), suggesting TCA may be the proximate metabolite producing this response. Dow and Green reported an increase in the concentration of 5-methyltetrahydrofolate (5-MTHF) in the plasma of rats treated with TCE-OH, suggesting a block in the cycling of 5-MTHF to tetrahydrofolate (THF). This pathway is under the control of the vitamin B12 –dependent methionine salvage pathway. We therefore treated rats with three daily doses of methylcobalamin (CH3Cbl) or hydroxocobalamin (OHCbl), a cofactor for methionine synthase, or L-methionine, followed by TCE (16mg/kg) to determine if they could alleviate the formic aciduria. These pre-treatments only partially reduced the excretion of formic acid in the urine. While prior treatment with S-adenosyl -L-methionine had no effect on formic acid excretion. Consistent, with these findings the activity of methionine synthase in the liver of TCE-treated rats was not inhibited. Transcriptomic analysis of the liver identified nine differential expressed genes, of note was down regulation of Lmbrd1 involved in the conversion of vitamin B12 into methylcobalamin (CH3Cbl) a cofactor for methionine synthase. Our findings indicate that the formic aciduria produced by TCE-OH and TCA may be the result of a block in the recycling of 5-MTHF to THF, the effect on the methionine salvage pathway being a secondary response following acute exposure.

Item Type: Article
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Pharmacy & Biomolecular Sciences
Publisher: The Korean Society of Toxicology (Springer)
Date Deposited: 26 Mar 2020 11:04
Last Modified: 26 Mar 2020 11:04
URI: http://researchonline.ljmu.ac.uk/id/eprint/12599

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