Enzymatic defluorination and metabolism of fluoroacetate, fluoroacetamide, fluoroethanol, and (-)-erythro-fluorocitrate in rats and mice examined by fluorine-19 and carbon-13 NMR

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Abstract
Fluoroacetate administered intraperitoneally (ip) to rats and mice is defluorinated to give fluoride ion evident in urine and kidney by 19F NMR. The use of [2-13C], [1,2-13C]-, and [1,2-14C]fluoroacetate, prepared from isotopically labeled glycine, combined with 13C NMR and TLC radioautography, respectively, reveals a complex mixture of urinary metabolites including an S-(carboxymethyl) conjugate complex in rats and mice and sulfoxidation products thereof in rats. Direct 13C NMR examination of the bile following treatment with [2-13C]fluoroacetate shows the presence of S-(carboxymethyl)glutathione or a related conjugate and an O-conjugate of fluoracetate. Incubation of [13C]fluoroacetate with rat and mouse liver cytosol involves formation of S-([13C]carboxymethyl) glutathione and fluoride ion. Fluorocitrate is also dtected by 19F NMR examination of fluoracetate incubations with mouse liver cytosol. Fluoroacetamide adminstered ip to rats and mice yields urinary fluoride ion formed via fluoroacetate which is liberated on hydrolysis by an organophosphate-sensitive amidase. 19F NMR chemical shifts of other metabolites of fluoroacetamide are consistent with fluoroacetohydroxamic acid in the liver of mice and fluorocitrate in the urine of rats. Fluoroethanol give s urinary fluoroacetate and fluoride ion in rats and mice and is converted to fluoroacetaldehyde by mouse and rat liver microsomes. (-)- and (+)-erythro-fluorocitrates administered ip to rats yield mostly the parent compounds in urine at 6 h with increasing amounts of fluoride ion thereafter. 19F NMR establishes that rat and mouse liver cytosols defluorinate (-)-erythro-fluorocitrate. Metabolic defluorination and pig heart aconitase also defluorinates (-)-erythro-fluorocitrate. Metabolic defluorination of fluoracetate and its progenitors, fluoroacetamide and fluoroethanol, is therefore attributable to both conjucation of fluoracetate with glutathione and conversion to (-)-erythro-fluorocitrate, which is both an inhibitor of and a substrate for aconitase. 13C NMR spectra of urine of rats and mice poisoned with fluoroacetate or (-)-erythro-fluorocitrate show elevated citrate and glucose and diminished urea consistent with disruptions in the tricarboxylic acid cycle and ammonia metabolism.