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PubMed1985

Covalent interaction of reactive metabolites with cytosolic coenzyme A as mechanism of haloethylene-induced acetonemia.

Previous experiments have shown that a number of xenobiotics such as halogenated ethylenes cause an experimental acetonemia. In addition, under exposure of rats to vinylidene fluoride (one of the agents producing this effect), the urinary excretion rates of acetoacetate and 3-hydroxybutyrate are enhanced. The enhanced formation of ketone bodies is theoretically explained by a covalent interaction of reactive metabolites of the applied xenobiotic with hepatic cytosolic coenzyme A. This theory is further corroborated by the following experiments: Microsomal incubations of [14C]vinyl chloride and [3H]coenzyme A lead to one metabolite containing 2 moles vinyl chloride/mole coenzyme A and two other with equimolar ratios of both components. Exposure of rats to vinyl chloride leads to a progressive depletion of hepatic cytosolic CoASH, but not of CoASH in mitochondria. In the cytosol acetyl-CoA is also diminished after vinyl chloride exposure. These changes may cause secondary effects in lipid metabolism which are regarded as responsible for the enhancement of ketone bodies.

Acetoacetates↗
PubMed1990

Investigations on the relationship between DNA ethenobase adduct levels in several organs of vinyl chloride-exposed rats and cancer susceptibility.

The levels of 1,N6-ethenodeoxyadenosine (epsilon dAdo) and 3,N4-ethenodeoxycytidine (epsilon dCyd) were measured in DNA of several target organs of vinyl chloride (VC)-exposed rats. Seven-day-old (group I) and 13-week-old (group II) BD VI rats were exposed during 2 weeks to 500 ppm VC in air (7 hr per day and 7 days per week). epsilon dAdo and epsilon dCyd were measured by a combination of prepurification of DNA hydrolysates by HPLC and competitive radioimmunoassay using specific murine monoclonal antibodies. Both ethenodeoxynucleosides were detected in liver, lungs and brain (levels ranging from 0.6 x 10(-7) to 1.3 x 10(-7) for epsilon dAdo/2'-deoxyadenosine and from 1.95 x 10(-7) to 4.92 x 10(-7) for epsilon dCyd/2'-deoxycytidine) but not in kidneys of group I rats. In group II rats, only liver DNA was analysed and the levels of each adduct were six times lower than in young (group II) rats. These findings are in good agreement with the organotropism and the age-related sensitivity of VC-induced carcinogenesis in rodents.

Aging↗
PubMed1975

The biological fate in rats of vinyl chloride in relation to its oncogenicity.

The main eliminative route for [14C]vinyl chloride after oral, i.v. or i.p. administration to rats is pulmonary; both unchanged vinyl chloride and vinyl chloride-related CO2 are excreted by that route and the other [14C] metabolites via the kidneys. After intragastric administration, pulmonary output of unchanged vinyl chloride is proportional to the logarithm of reciprocal dose. Excretion patterns after i.v. and i.p. injections are predictable from the characteristics of excretion following oral administration. Pulmonary excretion of unchanged vinyl chloride after oral dosing is complete within 3-4 h, but pulmonary elimination of CO2 and renal excretion of metabolites occupies 3 days. In comparison, 99% of a small i.v. dose is excreted unchanged within 1 h of injection; 80% within 2 min. The rate of elimination of a single oral doses of [14C]vinyl chloride is uninfluenced by up to 60 days' chronic dosing with the unlabelled substance. The distribution volume of vinyl chloride as displayed by whole-animal autoradiography agrees with deductions from excretion data. Small localization of 14C in the para-auricular region of appropriate sections occurs in sectioned tubules, belonging possibly to the Zymbal glands. Biotransformation of vinyl chloride into S-(2-chloroethyl) cysteine and N-acetyl-S-(2-chloroethyl) cysteine occurs through addition of cysteine, and biotransformation into: (i) chloroacetic acid, thiodiglycollic acid and glutamic acid, and (ii) into formaldehyde (methionine, serine), CO2 and urea is explicable in terms of an associative reaction with molecular O2 involving a singlet oxygen bonded transition state in dynamic equilibrium with a cyclic peroxide ground state. There is no evidence for chloroethylene oxide formation. Thiodiglycollic acid is the major metabolite of chloroacetic acid in rats; more than 60% of the dose. The interaction of vinyl chloride and of its primary metabolites with the intermediates of mammalian metabolism is discussed in relation to the oncogenicity of that substance.

Acetates↗
PubMed1978

Interactions of vinyl chloride with rat-liver DNA in vivo.

9beta-D-2'-Deoxyribofuranosyl-imidazo-[2,1-i]purine ("etheno-deoxyadenosine") and 1beta-D-2'-deoxyribofuranosyl-1,2-dihydro-2-oxo-imidazo-[1,2-c]pyrimidine ("etheno-deoxycytidine") are identified in the enzyme hydrolysates obtained (i) from calf-thymus DNA which had been modified by chemical reaction with chloroacetaldehyde and (ii) from liver DNA prepared from rats which had been exposed orally to vinyl chloride in their drinking water (250 ppm) for approx. 2 years. Thus, vinyl chloride-derived chloroethylene oxide and/or chloroacetaldehyde behaves as a bifunctional alkylating agent towards deoxyadenosine and deoxycytidine residues of DNA. The separation of deoxyribonucleosides and the two etheno-deoxyribosyl-nucleosides by liquid chromatography, and the mass spectra of etheno-deoxyadenosine and etheno-deoxycytidine and of their O-bis-(trimethylsilyl) derivatives are described. In the animal experiment (ii), the resulting proportion of etheno-deoxyadenosine is small compared with that of etheno-deoxycytidine. Imidazo-[2,1-i]purine (etheno-adenine) is identified: (a) in the supernatant after sedimentation of the modified DNA in the model experiment (i), and (b) in the product resulting from the reaction between chloroacetaldehyde and deoxyadenosine. The effect on the structure of DNA of the imidazo-cyclization of deoxyadenosine and deoxycytidine residues and of the depurination of etheno-deoxyadenosine residues is discussed in relation to vinyl chloride oncogenicity.

Acetaldehyde↗
PubMed1978

Vinyl chloride and vinyl benzene (styrene)--metabolism, mutagenicity and carcinogenicity.

Vinyl chloride and vinyl benzene (styrene) are mutagenic in microbial tests, in Drosophila, in yeast, and in mammalian cells. Reports from various countries have shown an excess of chromosomal aberrations in the lymphocytes of workers exposed to vinyl chloride monomer when the workers were compared with controls. Workers occupationally exposed to styrene also revealed a clear increase in the rate of chromosome aberrations in their lymphocytes. Both chloroethylene oxide and styrene oxide, the primary biotransformation products of vinyl chloirde and styrene respectively, bind covalently to cellular macromolecules. Vinyl chloride is a carcinogen in both animals and man. Styrene is currently being tested in animals. These findings, the demonstration of mutagenic response via microbial and other test systems and with observations of significant excesses of chromosomal aberrations among workers exposed to these agents, raise scientific and health oriented concern about the possible genetic risks of vinyl chloride and styrene to man.

Animals↗
PubMed1979

Ethanol inhibition of vinyl chloride metabolism in isolated rat hepatocytes.

Isolated rat liver cells convert [14C]vinyl chloride into non-volatile metabolites. The metabolism is not increased by in vivo pretreatment with phenobarbital. It is sensitive to inhibition by ethanol, which at a concentration of 4 mM inhibits vinyl chloride metabolism to 50% in hepatocyte suspensions. The metabolic activity is NADPH-dependent and is localized in the microsomal fraction of the liver. The enzyme is also strongly inhibited by tetrahydrofuran, indicating that it could be identical to an ethanol-inducible cytochrome P-450 described in the literature [1].

Animals↗
PubMed1981

The metabolism of drugs and carcinogens in isolated subcellular fractions of Drosophila melanogaster. I. Activation of vinyl chloride, 2-aminoanthracene and benzo[a]pyrene as measured by mutagenic effects in Salmonella typhimurium.

The capacity of microsomal fractions from different Drosophila strains to activate three premutagens, 2-aminoanthracene (2-AA), vinyl chloride (VCM) and benzo[a]pyrene (BP) was investigated, using Salmonella typhimurium as the indicator organism. A significant increase in the mutation response in the Salmonella test system was obtained with all three substances in the presence of a metabolizing system (S9) from Drosophila larvae. 2-AA was converted to highly mutagenic metabolite(s) by the Drosophila S9 and the mutagenic effect was further increased after pretreatment with Aroclor 1254 (PCB) or beta-naphthoflavone (BNF). BP had only marginal mutagenic effects, causing less than a 2-fold increase in the number of mutants over the control. The data indicate that the metabolic conversion of BP is different in the Drosophila as compared to the rat liver microsomal fraction. In accordance with mutagenic data on Drosophila in vivo, vinyl chloride was a fairly weak mutagen in this Drosophila/Salmonella in vitro system.

Animals↗
PubMed1979

Identification of a non-specific carboxylesterase in human pancreas using vinyl 8-phenyloctanoate as a substrate.

Human pancreatic tissue, pancreatic juice and sera of patients suffering from acute pancreatitis contain a vinyl 8-phenyloctanoate hydrolysing activity which was separated from true pancreatic lipase (EC 3.1.1.3). The enzyme, preliminary called "non-specific pancreatic carboxylesterase, was partially purified from human pancreatic tissue by DEAE-cellulose chromatography. Its molecular weight was found to be 54 000 by gel filtration on Sephadex G-100. The isoelectric point was estimated as 4.65 by isoelectric focusing. The results explain the poor correlation obtained when determinations of "serum lipase activity" using triolein and vinyl 8-phenyloctanoate as substrates are compared. However, since non-specific pancreatic carboxylesterase is liberated into the serum, determination of this new enzyme provides additional information in the diagnosis of pancreatic diseases.

Caprylates↗