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At least 19 recordsLinked to original sources

PubMed1976

The mutagenicity of chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid, conceivable metabolites of vinyl chloride.

Previous investigations have shown that the carcinogen vinyl chloride causes base-pair substitution in the bacterium Salmonella typhimurium. The ability of four conceivable metabolites-chloroethylene oxide, chloroacetaldehyde, 2-chloroethanol and chloroacetic acid-to cause base-pair substitution directly in Salmonella typhimurium TA1535 has been compared. The main comparison was performed at initial concentrations from 0.1 to 1.5 mM. In this region, however, a mutagenic effect was observed only with chloroethylene oxide and chloroacetaldehyde, the former being approximately 20 times more effective than the aldehyde when compared on a molar basis.2-Chloroethanol and chloroacetic acid were studied also at higher concentration (1 mM-1 M), and a weak mutagenic response was found with 1 M 2-chloroethanol solution. With chloroacetic acid no enhancement of the mutation frequency could be detected. Chloroethylene oxide was found to be approximately 450 times more effective as a mutagen than chloroacetaldehyde when the comparison is based on exposure doses, defined as the time-dependent concentrations of the compounds in the treatment solutions, integrated between the times of onset and termination of treatment. Similarly, chloroethylene oxide was 10,000-15,000 times more effective as a mutagen than ethylene oxide, used as a positive control.

Acetaldehyde↗

PubMed1980

Carcinogenicity of chloroethylene oxide, an ultimate reactive metabolite of vinyl chloride, and bis(chloromethyl)ether after subcutaneous administration and in initiation-promotion experiments in mice.

Repeated s.c. administration of chloroethylene oxide, a reactive metabolite of the carcinogen vinyl chloride, induced local tumors in mice, with an incidence comparable to that of bis(chloromethyl)ether, a structurally related human and animal carcinogen, when both compounds were applied at maximum tolerated chronically toxic doses; no tumors distant from the injection site were produced. Bis(chloromethyl)ether, chloroethylene oxide, and its rearrangement product chloroacetaldehyde, a highly toxic compound, were further tested in an initiation-promotion experiment. Application to the skin of a single dose of either bis(chloromethyl)ether or chloroethylene oxide, followed by 3-times-weekly applications of 12-O-n-tetradecanoylphorbol-13-acetate for 42 weeks, produced skin tumors in mice; chloroacetaldehyde under comparable conditions produced no increase in benign or malignant tumors. A good correlation between the chemical reactivity, on the basis of hydrolysis constants in aqueous media, and the carcinogenicity of the three compounds was noted. Our results support the hypothesis that epoxidation of the thylenic double bond in vinyl chloride yields an ultimate carcinogenic metabolite, chloroethylene oxide, a highly reactive compound which appears also to be largely responsible for the known genetic changes caused by the parent compound.

Animals↗

PubMed1977

The effect of vinyl chloride monomer, chloroethylene oxide and chloracetaldehyde on DNA synthesis in regenerating rat liver.

Vinyl chloride monomer used in the manufacture of polyvinyl chloride is a chemical of increasing industrial importance but has recently been incriminated as a carcinogen, producing a mutagenic effect after being metabolized to active metabolites. The initial effect of vinyl chloride monomer and two of its presumed metabolites, chloracetaldehyde and chloroethylene oxide, on DNA synthesis was investigated in vivo in regenerating rat liver. The established control curve for the DNA synthesis rate after partial hepatectomy demonstrated two waves of synthetic activity at 21 and 30 h. Vinyl chloride, injected intravenously immediately on completion of the operation, depressed the first wave of DNA synthesis by 49.6%. The second peak of DNA synthetic activity was similar to that of the control. Chloracetaldehyde and chloroethylene oxide both produced similar effects on the first wave of DNA synthesis after partial hepatectomy, inhibiting the DNA synthesis rate by approx. 50%. After a regenerating period of 27 h, however, they produced very different effects, chloroethylene oxide raising the control DNA synthesis rate at 30 h by 49% while chloracetaldehyde tended to desynchronize the well-defined second peak of the control. The test compounds have been compared to literature reports of the inhibitory effects of various carcinogens on DNA synthesis.

Acetaldehyde↗

PubMed1985

Mutagenicity and toxicity of chloroethylene oxide and chloroacetaldehyde.

Exposure of several trp-auxotrophic Escherichia coli strains, carrying base-pair substitutions, to chloroethylene oxide or chloroacetaldehyde (two metabolites of vinyl chloride) increased the mutation frequency to tryptophan prototrophy. Strong cytotoxic and mutagenic effects were observed with 2.5 mM chloroethylene oxide, while a higher concentration of chloroacetaldehyde (100 mM) exhibited a mutagenic effect which was 400 times lower.

Acetaldehyde↗

PubMed1975

Mutation induction in Chinese hamster V79 cells by two vinyl chloride metabolites, chloroethylene oxide and 2-chloroacetaldehyde.

Chloroethylene oxide and 2-chloroacetaldehyde, two possibly carcinogenic metabolities of vinyl chloride in mammals, caused a dose-dependent induction of 8-azaguanine- and ouabain-resistant mutants in Chinese hamster V79 cells in vitro. Up to one-hundred-fold higher concentrations of 2-chloroethanol or monochloroacetic acid, a urinary vinyl chloride metabolite in rats and man, were inactive.

Acetaldehyde↗

PubMed1998

Kinetic characterization of CYP2E1 inhibition in vivo and in vitro by the chloroethylenes.

Trans- and cis-1,2-dichloroethylene (DCE) isomers inhibit their own metabolism in vivo by inactivation of the metabolizing enzyme, presumably the cytochrome P450 isoform, CYP2E1. In this study, we examined cytochrome P450 isoform-specific inhibition by three chloroethylenes, cis-DCE, trans-DCE, and trichloroethylene (TCE), and evaluated several kinetic mechanisms of enzyme inhibition with physiological models of inhibition. Trans-DCE was more potent than cis-DCE, and both were much more effective than TCE in inhibiting CYP2E1. The kinetics of in vitro loss of p-nitrophenol hydroxylase (pNP-OH) activity (a marker of CYP2E1) in microsomal incubations and of the in vivo gas uptake results were most consistent with a mechanism in which inhibition of the metabolizing enzyme (CYP2E1) was presumed to be related to interaction of a reactive DCE metabolite with remaining substrate-bound, active CYP2E1. The kinetics of inhibition by TCE, a weak inhibitor in vitro, were very different from that of the dichloroethylenes. With TCE, parent compound concentrations influenced enzyme loss. Trans-DCE was a more potent inhibitor of CYP2E1 than cis-DCE based on both in vivo and in vitro studies. Quantitative differences in the inhibitory properties of the 1,2-DCE isomers may be due to the different stability of epoxides formed from bioactivation by CYP2E1. Epoxide intermediates of DCE metabolism, reacting by water addition, would yield dialdehyde, a potent cross-linking reagent.

Animals↗

PubMed1978

Pesticide-induced changes in hepatic microsomal enzyme systems: further studies on the effects of 1,1,-di(p-chlorophenyl)-2-chloroethylene (DDMU) in the Japanese quail.

Changes in the liver resulting from the low level dietary administration of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU),p,p'-DDT, o,p'-DDT, p,p'-DDD and p,p'-DDE to Japanese Quail have been monitored. DDMU was exceptional in causing substantial increases in relative liver wt. and hepatic glucose-6-phosphatase after feeding at 100 ppm for 28 days. The time course of liver enzyme induction by DDMU has also been studied in Japanese Quail after periods of dietary administration ranging from 1--28 days with particular reference to changes in hepatic cytochrome P-450 and relative liver wt. Structural changes in the liver have been followed by reference to protein and lipid components. The hepatic response to DDMU appears to be biphasic. Initially there are substantial increases in hepatic cytochrome P-450 and relative liver wt., but the latter is largely due to accumulation of triglycerides. After approximately 20 days the level of hepatic cytochrome P-450 remain at a high 'plateau' level. This secondary phase of liver induction probably involves cell proliferation. It is concluded that DDMU causes major changes in the avian liver and either directly or through a metabolite causes pronounced microsomal enzyme induction.

Animals↗

PubMed1979

The effects of 1,1-di(p-chlorophenyl)-2-chloroethylene on plasma enzymes and blood constituents in the Japanese quail.

Glutamate oxaloacetate transminase (GOT), glutamate dehydrogenase (GDH), sorbitol dehydrogenase (SDH), pseudo-cholinesterase (ChE) and various blood constituents were measured in the plasma of Japanese quail fed 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU) at low levels for periods ranging from 2 to 32 days. Previous work has shown that DDMU is a potent inducer of hepatic microsomal enzymes causing marked structural changes in the liver. A rapid increase in plasma GOT was observed within 4 days accompanied by an increase in relative liver weight. Plasma GDH and SDH increased to a maximum between 16 and 24 dyas which seems to be associated with hepatic cell proliferation. Plasma ChE showed a steady increase over the time course of DDMU administration. The level of plasma lipid was reduced after 4 days whereas the hepatic lipid content was substantially increased suggesting that the fatty liver condition may be caused by decreased release of triglyceride from the liver. Plasma glucose was reduced at 8 days but there was no evidence of a hyperglycaemic state. The changes noted after 2 days of DDMU diet were confirmed by measurements on birds 18 h after oral dosing the DDMU. The study demonstrates the value of plasma enzyme measurements for the early detection of toxic effects and indicates that DDMU administration leads to extrahepatic effects in addition to those previously described in the liver.

Animals↗

PubMed1983

Metabolism and relative carcinogenic potency of chloroethylenes: a quantum chemical structure-activity study.

Properties of six chloroethylenes which could serve as indicators of their relative metabolic behavior and carcinogenic activity have been calculated using Modified Neglect of Diatomic Overlap (MNDO), a semiempirical, all valence electron, molecular orbital method. Possible pathways of transformation of parent compounds to acylchlorides, chloroaldehydes and epoxides--their putative ultimate carcinogens--were considered, and heats of formation and relative stabilities of intermediates were calculated. Our results indicate that carbonyl compounds could be formed with and without the intermediacy of epoxides, suggesting the possibility of more than one pathway in activation of parent compounds. Electronic properties of carbonyl products and epoxide carbocations, putative ultimate carcinogens which could serve as indicators of their relative electrophilicities, were also calculated. The results obtained indicated that the relative extent of metabolism to carbonyl products, rather than their electrophilicity, is a determinant of the relative carcinogenic activity of the parent compound. Of the various thermodynamic criteria investigated, four were found to be indicators of both relative metabolic behavior and carcinogenic activity.

Animals↗

PubMed1990

Nucleophilic selectivity and reaction kinetics of chloroethylene oxide assessed by the 4-(p-nitrobenzyl)pyridine assay and proton nuclear magnetic resonance spectroscopy.

The nucleophilic selectivity (Swain-Scott's constant s) of chloroethylene oxide (CEO), an ultimate carcinogenic metabolite of vinyl chloride, was determined to be 0.71 using the 4-(p-nitrobenzyl)pyridine (NBP) assay (Spears method). The molar extinction coefficient of the adduct formed between NBP and CEO was measured; and the second-order rate constants for the reactions of CEO with NBP and with thiosulfate were estimated at three temperatures. The disappearance of CEO and the formation of chloroacetaldehyde (CAA) and glycolaldehyde (GCA) were followed in D2O or a mixture of D2O/hexadeuterated acetone (acetone-d6), using Fourier transform proton nuclear magnetic resonance spectroscopy (1H-FTNMR). Evidence was obtained that CEO reacts with chloride ions to yield CAA at a rate constant of about 17 M-1 h-1 in D2O/acetone-d6 (1 : 1, v/v) at 280 K. Under the same conditions, the first-order rate constant kr for the thermal rearrangement of CEO into CAA was estimated to be approximately 0.41 h-1. These data suggest that the isomerization of CEO may be a minor reaction in physiological saline. These chemical properties of CEO are discussed in relation to the mechanism of vinyl chloride-induced carcinogenesis.

Acetaldehyde↗

PubMedDate not supplied

Induction of specific base-pair substitutions in E. coli trpA mutants by chloroethylene oxide, a carcinogenic vinyl chloride metabolite.

Chloroethylene oxide (CEO), an ultimate carcinogenic metabolite of vinyl chloride, induces base-pair substitution mutations but not frameshift mutations in bacteria. The mutational specificity of CEO was investigated in Escherichia coli, using the trpA mutants developed by Yanofsky. Reversion frequencies to tryptophan prototrophy were analysed, and CEO was found to induce more GC----AT transitions than AT----TA transversions, in addition to a low frequency of other types of substitution. This specificity indicates that CEO is mutagenic through a miscoding DNA adduct. The results are discussed in relation to the various CEO-DNA adducts formed and to their reported or expected mispairing properties.

Alleles↗

PubMedDate not supplied

recA-independent mutagenicity induced by chloroethylene oxide in E. coli.

The mechanism of mutagenicity of chloroethylene oxide (CEO), an ultimate carcinogenic metabolite of vinyl chloride, was investigated in 3 Escherichia coli strains (E. coli "multitest"). In this system, the mutagenicity of CEO was found to be mainly SOS-independent. CEO did not induce recombinational events at a detection level of about 10(-2) recombinants/survivor. Our results indicate that CEO- (or vinyl chloride-) induced bacterial mutagenesis arises mainly from miscoding DNA adducts.

Escherichia coli↗

PubMed1983

The effects of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU) on hepatic morphology of Japanese quail.

The effects of dietary administration of 1,1-di(p-chlorophenyl)-2-chloroethylene (DDMU) to Japanese quail at a concentration of 100 ppm were investigated for periods of up to 32 days. Hepatic morphology was studied by light microscopy. Histologic changes observed included cytoplasmic and nuclear degeneration in the hepatocytes followed by severe lipid accumulation and hepatocellular hypertrophy. There was a progressive increase in cytoplasmic vacuoles containing lipid up to Day 24 followed by a decrease by Day 32 when the numbers of vacuoles remained greater than those in untreated quail livers. The vacuoles showed a distribution which followed the functional acinar units of the liver. Increased numbers and hypertrophy were observed in Kupffer cells and fibrocytes. There was an occasional necrotic hepatocyte observed but this lesion was not a prominent feature. Hepatocellular hyperplasia occurred as the lipid accumulation decreased. The histologic findings are compared with the biphasic response previously described.

Animals↗

PubMedDate not supplied

New adducts of chloroethylene oxide and chloroacetaldehyde with pyrimidine nucleosides.

Pyrimidine nucleosides were treated with chloroethylene oxide (CEO) and 2-chloroacetaldehyde (CAA) in methanol and, following trimethylsilylation, the products were analysed by combined gas chromatography-mass spectrometry (GC-MS). Reaction of CEO with 2'-deoxycytidine gave 3,N4-etheno-2'-deoxycytidine and diadduct isomers in which a 1-hydroxy-2-chloroethyl group was substituted for hydrogen on either deoxyribose hydroxyl group. When the N-3-position of 2'-deoxycytidine was blocked by a methyl group, CEO or CAA added a 2-chlorovinyl group at the exocyclic N4 amino nitrogen, as evidenced by a pair of cis/trans isomers. Reaction of 3-methylcytidine and CEO also gave the cis/trans 2-chlorovinyl base adducts, as well as six isomers with a 1-hydroxy-2-chloroethyl group attached to ribose and nine isomeric diadducts, which are possibly positional and optical isomers. Although CEO and CAA were less reactive towards uracil in 3-methyluridine than to cytosine in 3-methyl(deoxy)-cytidine, both electrophiles were able to alkylate 3-methyluridine on ribose, yielding 1-hydroxy-2-chloroethyl derivatives. These data suggest that CEO and CAA may also yield non-cyclic adducts with cytosine in double-stranded DNA where the N-3 position is of low accessibility. Such adducts are of interest in view of their potential promutagenic properties. The data also imply a new mechanism of reaction of CEO with nucleophiles.

Acetaldehyde↗

PubMed2006

Chemical reactivity as a tool to study carcinogenicity: reaction between chloroethylene oxide and guanine.

Chloroethylene oxide, an ultimate carcinogen of vinyl chloride, reacts with DNA giving rise to 7-(2-oxyethyl)guanine adduct in a nearly quantitative yield. This reaction represents an initial step of carcinogenesis associated with vinyl chloride. From experimental data for this reaction we calculated the second-order rate constant of 0.049 s(-1) M(-1), which corresponds to the activation free energy of 19.5 kcal/mol. We also performed a series of medium high ab initio and density functional theory simulations. Effects of hydration were considered in the framework of the Langevine dipoles solvation model and the solvent reaction field method of Tomasi and co-workers. In silico calculated activation free energies are in a good agreement with the experimental value. This fact presents strong evidence in favor of the validity of the proposed reaction mechanism and points to the applicability of quantum-chemical methods to studies of other reactions associated with carcinogenesis. Insignificant stereoselectivity of the studied reaction was also predicted.

Carcinogens↗

PubMed1997

Mutagenicity of vinyl chloride and its reactive metabolites, chloroethylene oxide and chloroacetaldehyde, in a metabolically competent human B-lymphoblastoid line.

Vinyl chloride (VC), a known human and rodent carcinogen, is metabolically activated by cytochrome P450 to chloroethylene oxide (CEO), which can rearrange to chloroacetaldehyde (CAA) or undergo hydrolysis. To further understand the roles of CEO and CAA in VC mutagenesis, the types and frequencies of mutations induced at the hypoxanthine (guanine) phosphoribosyl-transferase (hprt) locus were examined in a human B-lymphoblastoid line constitutively expressing human cytochrome P450 2E1 (H2E1 cells). VC was toxic and mutagenic to H2E1 cells as a function of incubation time; exposure to 7.5% VC in air resulted in 75% survival and an hprt mutant frequency of 42 x 10(-6) after 48 h, compared to 5.7 +/- 2.7 x 10(-6) for unexposed cells. The exposure of H2E1 cells to 0.8 to 15.0% VC in air produced similar mutant frequencies without a clear dose-response relationship, suggesting saturation of metabolic activation. Both CEO and CAA exhibited dose-dependent increases in cell killing and mutant frequency in H2E1 cells. Treatment with 16 microM CEO for 24 h resulted in 75% survival and an induced mutant frequency of 23 x 10(-6), while 16 microM CAA produced 5% survival and an induced mutant frequency of 20 x 10(-6). Structural alterations at the hprt locus in independent thioguanine-resistant clones were examined by Southern blot analysis of Pst I-digested DNA with a full-length human hprt cDNA probe. Ten percent (5/50) of VC-induced and 18% (7/38) of CEO-induced mutants showed detectable deletions, compared with 45% (9/20) of CAA-induced mutants. Thus, VC and CEO displayed similar toxicity/mutation profiles and a similar frequency of large deletions, whereas CAA displayed greater toxicity and a larger frequency of deletion mutations. These results suggest that the majority of mutations induced by VC occur through its metabolite, CEO.

Acetaldehyde↗

PubMed1998

Detection of 1,N6-ethenoadenine in rat urine after chloroethylene oxide exposure.

The four etheno adducts of vinyl chloride formed in DNA, 1,N6-ethenoadenine (epsilonA), 3,N4-ethenocytosine, 1,N2-ethenoguanine and N2,3-ethenoguanine were previously reported to be released from DNA by a family of enzymes in the base-excision repair pathway (Dosanjh et al., Proc. Natl Acad. Sci. USA, 91, 1024-1028, 1994; Hang et al., Carcinogenesis, 17, 155-157, 1996; Hang et al., Proc. Natl Acad. Sci. USA, 94, 12869-12874, 1997). Adducts excised from DNA by glycosylases are usually excreted in urine and have been reported to be potential biomarkers of DNA damage in exposed individuals. In this study, we report the detection of epsilonA in the urine of rats exposed to chloroethylene oxide (CEO) using immunoaffinity columns made with specific monoclonal antibodies for enrichment, followed by quantitation by HPLC with fluorescence detection. Chemical analysis of urine samples revealed the presence of a compound chromatographically identical to authentic epsilonA standard. This compound was confirmed by mass spectral analysis. EpsilonA was present in urine of control and CEO-treated rats, with the latter having up to 50-fold greater amounts. The cumulative excretion of epsilonA reached a plateau between 24 and 48 h post-exposure. While it is clear that CEO treatment results in increased excretion of epsilonA, the exact source of the adduct is unknown. When rats were administered epsilonA i.v., approximately 10% of the administered dose was excreted in urine. This research demonstrates that urinary excretion of epsilonA may be a potential biomarker for in vivo alkylation of DNA and nucleotide pools.

Adenine↗

PubMed1981

Modification of deoxyguanosine by chloroethylene oxide.

Reaction of deoxyguanosine in glacial acetic acid with chloroethylene oxide, a proposed reactive metabolite of vinyl chloride, led to a single, strongly fluorescent product in nearly quantitative yield. The u.v. spectra indicated alkylation of N-7 of guanine, which was confirmed following reduction of the reaction product by sodium borohydride to 7-(2-hydroxyethyl)guanine, and the synthesis of the same modified guanine via a stereoselective 7-N hydroxy alkylation using 2,3-epoxy-1-propanol. In agreement with the expected structure 7-(2-oxoethyl)guanine reacted with the carbonyl specific reagent 2,4-dinitrophenylhydrazine (2,4-DNPH). However, its i.r. and proton n.m.r. spectra did not support the existence of a simple aldehyde group. Moreover, the 2,4-dinitrophenylhydrazone was labile, 7-(2-oxoethyl)guanine being produced when excess 2,4-DNPH was removed. This instability was interpreted as being due to the reversible formation of a hemiacetal ring between O6 of the guanine residue and the aldehyde carbon of the 2-oxoalkyl group resulting in O6,7-(1'-hydroxyethano)guanine. This conformation was supported by the occurrence in field desorption mass spectra of the ions of m/e = 175 and 292 which are interpreted as O6,7-ethenoguanine and O6,7-ethenodeoxyguanosine resulting from the elimination of H2O of the hydroxyethano residue. O6,7-(1'-hydroxyethano)guanine might be expected to cause faulty base pairing during replication of DNA, which may be the molecular basis of the carcinogenicity of vinyl chloride.

Borohydrides↗