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 16 mg/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 (16 mg/kg) to determine if they could alleviate the formic aciduria. These pretreatments only partially reduced the excretion of formic acid in the urine. Although 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 downregulation of Lmbrd1 involved in the conversion of vitamin B12 into 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.

中文翻译：

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三氯乙烯代谢物对大鼠肝脏维生素B12依赖的蛋氨酸挽救途径的影响及其与大鼠甲酸排泄增加的相关性。

工业溶剂三氯乙烯（TCE）及其两种主要代谢物三氯乙醇（TCE-OH）和三氯乙酸（TCA）引起雄性F344大鼠甲酸尿尿。先用1-氨基苯并三唑a细胞色素P450抑制剂再用TCE（16mk / kg，口服）治疗雄性F344大鼠，完全预防了甲酸尿症，但对TCA产生的甲酸排泄（8或16 mg / kg， po），表明TCA可能是产生此反应的最接近的代谢产物。陶氏和格林报道了用TCE-OH治疗的大鼠血浆中5-甲基四氢叶酸（5-MTHF）的浓度增加，表明5-MTHF向四氢叶酸（THF）循环的阻滞。此途径受维生素B12依赖的蛋氨酸挽救途径的控制。因此，我们用三日剂量的甲钴胺（CH3Cbl）或羟考拉巴明（OHCbl）（蛋氨酸合酶或L-蛋氨酸的辅因子），然后用TCE（16 mg / kg）处理大鼠，以确定它们是否可以缓解甲酸尿症。这些预处理仅部分减少了尿液中甲酸的排泄。尽管先前用S-腺苷-L-蛋氨酸治疗对甲酸排泄没有影响。与这些发现一致，TCE治疗的大鼠肝脏中蛋氨酸合酶的活性未受到抑制。值得注意的是，肝脏鉴定的9个差异表达基因的转录组学分析是Lmbrd1的下调，参与了维生素B12到甲硫氨酸合酶辅因子CH3Cbl的转化。