Tetrachloroethylene Oxide:  Hydrolytic Products and Reactions with Phosphate and Lysine

Abstract

Tetrachloroethylene, or perchloroethylene (PCE), has considerable industrial use and is of toxicological interest because of a variety of effects. Most of the existing literature presents PCE oxide as a critical intermediate in the oxidative metabolism of PCE to Cl(3)CCO(2)H, oxalic acid, and products covalently bound to proteins, including trichloroacetyl derivatives of lysine. PCE oxide was synthesized by photochemical oxidation of PCE and characterized. Decomposition at neutral pH (t(1/2) = 7.9 min at 0 degrees C, 5.8 min at 23 degrees C, 2.6 min at 37 degrees C) yielded only trace ( approximately 1%) Cl(3)CCO(2)H; the major products identified were CO (73% yield) and CO(2) (63% yield). In phosphate buffer (0.10 M) a major product was identified as oxalyl phosphate. Oxalyl chloride also reacted to form CO and CO(2) in aqueous solution and to form oxalyl phosphate in neutral phosphate buffer. Oxalyl phosphate decomposed to oxalic acid (t(1/2) = 53 min at 37 degrees C) but did not react with lysine. Reaction of PCE oxide with free lysine yielded the oxalic acid amide derivatives of lysine plus lysine dimers in which cross-linking of the amino groups involved oxalo linkage. The reaction of PCE oxide with albumin yielded mainly N(6)-oxalolysine and some (<5%) N(6)-trichloroacetyllysine. We propose a reaction pathway for PCE oxide based on our previous studies with trichloroethylene oxide, in which C-C bond scission is a major product of reaction in aqueous buffer and yields CO and CO(2). Oxalyl species are proposed as intermediates and prominent acylating species formed in the reactions of the epoxide. The formation of Cl(3)CCO(2)H in cytochrome P450 reactions is postulated to result from intramolecular migration within an enzyme intermediate.

Formation and Cleavage of C–C Bonds by Enzymatic Oxidation–Reduction Reactions

“…​ Similarly, P450 2E1 converts tetrachloroethylene to an epoxide, which also breaks down through 1,2-chloride shift and hydrolytic pathways, leading to the formation of CO and CO 2 299 (Figure 84).…”

Human Health Effects of Tetrachloroethylene: Key Findings and Scientific Issues

“…Oxidation (Figure 1, left) occurs predominantly in the liver to a ferric-oxide (Fe-O) intermediate, the primary fate of which is thought to be trichloroacetyl chloride (TCAC), which then hydrolyses to yield trichloroacetic acid (TCA). A secondary fate of oxidation is the epoxide (PCE-O), which decomposes to ethandioyl dichloride (EDD) and then to carbon monoxide (CO) and carbon dioxide (CO 2 ) (Yoshioka et al 2002). Oxalic acid (OXA) has been reported as both an in vivo and in vitro product of PCE oxidation (Pegg et al 1979; Yoshioka et al 2002) and may be derived either from the epoxide or directly from the Fe-O intermediate.…”

“…A secondary fate of oxidation is the epoxide (PCE-O), which decomposes to ethandioyl dichloride (EDD) and then to carbon monoxide (CO) and carbon dioxide (CO 2 ) (Yoshioka et al 2002). Oxalic acid (OXA) has been reported as both an in vivo and in vitro product of PCE oxidation (Pegg et al 1979; Yoshioka et al 2002) and may be derived either from the epoxide or directly from the Fe-O intermediate. PCE conjugation with GSH (Figure 1, right) in the liver or kidney forms trichlorovinyl glutathione (TCVG), which is further processed by γ-glutamyl transpeptidase (GGT) and cysteinylglycine dipeptidase (DP) in the kidney, forming the cysteine conjugate S -trichlorovinyl- l -cysteine (TCVC).…”

Cytochrome P450s and other enzymes in drug metabolism and toxicity

“…49 The study also found that oxalyl chloride, the rearrangement product derived from perchloroethylene oxide, reacts not only with proteins but also with phosphate. The product, oxalyl phosphate, is relatively stable and can be isolated ( t 1/2 ~100 minutes); it does not react with proteins.…”

“…The product, oxalyl phosphate, is relatively stable and can be isolated ( t 1/2 ~100 minutes); it does not react with proteins. 49 These results are of interest given the large number of bioactivation studies that have been done using high concentrations of phosphate buffer (eg, 100 mM).…”