Evidence of chloroethylene oxide being the reactive metabolite of vinyl chloride towards DNA: comparative studies with 2,2′ -dichloro-diethylether

Abstract

The roles of chloroethylene oxide (CEO) and chloroacetaldehyde (CAA) in carcinogenicity of vinyl chloride (VC) have been studied by comparing biological effects of VC exposure with those of 2,2'-dichlorodiethylether (bis(chloroethyl)ether, BCEE) as a metabolic precursor of CAA. Biological end-points investigated were covalent protein binding, nucleic acid (RNA and DNA) alkylation and the potency of the two chemicals to induce preneoplastic ATPase-deficient foci in rat liver. After exposure of rats to [1-14C]BCEE, BCEE derived radioactivity was bound to liver proteins. Analysis of hydrolysates of liver RNA and DNA gave no indication for the formation of either 7-N-(2-oxoethyl)guanine, 1,N6-ethenoadenine or 3,N4-ethenocytosine residues within the nucleic acids. After application of VC, BCEE or chloroethanol [CE), also a precursor of CAA) to young rats, only animals exposed to VC developed preneoplastic hepatocellular ATPase-deficient foci. From these investigations it is concluded, that CEO (which is not formed during metabolism of BCEE and CE), not CAA, is the ultimate carcinogenic principle in VC carcinogenicity.

Roles of the vinyl chloride oxidation products 2-chlorooxirane and 2-chloroacetaldehyde in the in vitro formation of etheno adducts of nucleic acid bases

“…l-Chlorooxirane was shown to react with calf thymus DNA to form both lA/6ethenoadenosine and AP.S-ethenoguanine considerably more effectively than did 2-chloroacetaldehyde in experiments where the reaction was quenched after 10 half-lives of the epoxide (5) (Figure 2). The lack of formation of N1 -(2-oxoethyl)guanine from 2-chloroacetaldehyde is consistent with the reported absence of its in vivo formation with chemicals that generate this electrophile through metabolism (4,30).…”

Vinyl Chloride—A Classical Industrial Toxicant of New Interest

“…The latter yields chloroacetaldehyde as intermediate metabolite, but not chloroethylene oxide. By this way it was concluded (Gwinner et al, 1983) that the biologically relevant alkylating agent was in fact the epoxide metabolite, chloroethylene oxide. This was later confirmed by independent ways (Guengerich, 1992).…”

Etheno adducts: from tRNA modifications to DNA adducts and back to miscoding ribonucleotides

“…7 , Table 1 ) [ 27 ]. Gwinner et al [ 36 ] reported that 2,2′-dichlorodiethyl ether, which is hydroxylated and decomposes to 2-chloroacetaldehyde, did not yield etheno DNA adducts or N 7 -(2-oxoethyl) dGuo when given to rats nor did it produce the preneoplastic foci, a hallmark of vinyl chloride carcinogenesis. The results were congruent with in vitro results on the labeling of DNA by 14 C-vinyl halides in microsomal reactions, with the epoxides and 2-haloacetaldehydes being quenched by the addition of enzymes (epoxide hydrolase and alcohol dehydrogenase) (Fig.…”

“…7 ). The results have biological relevance in that other chemicals that can generate 2-haloacetaldehydes after metabolism are not very carcinogenic [ 36 ] (Fig. 7 ).…”