Vinyl chloride metabolism

Hartmans S, JAM de Bont (1992) Aerobic vinyl chloride metabolism in Mycobacterium aurum LI. Appl Environ Microbiol 58 1220-1226. 

E. Arrhenius (1979). Ethanol inhibition of vinyl chloride metabolism in isolated rat hepatocytes. Chem. Biol. Interact. 25, 1-6. 

Figure 6. The ratio between the amount of vinyl chloride metabolized (micrograms M) and the concentration of inhaled vinyl chloride (ppm VC) in rats Data points are mean standard deviation and the solid line was drawn by...

Evidence that vinyl chloride is carcinogenic in expmimental animals and humans [5,6], led to numerous studies concerning mammalian vinyl chloride metabolism and resulted in classification of vinyl diloride as a priority pollutant by the U.S. Environmental Protection Agency. 

In the mid 1970 s, a number of publications appeared that demonstrated that vinyl chloride induced angiosarcoma of the liver in workers in the polyvinyl chloride manufacturing industry [5,7]. Subsequently, a number of biochemical studies, focussing on vinyl chloride metabolism in the liver, were published. Barbin et al. [8] demonstrated that, in Ihe presence of oxygen and NADPH, vinyl chloride was transformed to... 

The presence of alkene monooxygenase activity in extracts of vinyl chloride-grown M. aurum LI, combined witli the observation that vinyl chloride degradation can be competitively inhibited by the addition of ethene or propene, which are both oxidized to the corresponding epoxides, is strong evidence that the initial step in vinyl chloride metabolism is indeed catalyzed by alkene monooxygenase (Figure 3) [25]. 

Figure 3. The initial step in vinyl chloride metabolism of M, aurum LI, catalyzed by alkene monooxygenase.

Interestingly, the initial step in vinyl chloride metabolism in Mycobacterium aurum LI is the same as in mammalian liver. Unfortunately, as is the case in mammals, Uie further metabolism of the extremely toxic and reactive chlorooxirane is still obscure. It will probably, also prove to be very difiBcult to elucidate this step in strain LI, in view of the very low stability of the enzymatic activity responmble for the further transformation of chlorooxirane. 

Acute inhalation exposure of rats to 200,000 ppm VF for 30 minutes or more produced weak anaesthesia and no deaths (90). In rats VF is only slightly metabolized at a rate of one-fifth that of vinyl chloride (91—95). An extensive program of toxicity testing of vinyl fluoride is ia progress (96,97). 

Barton HA, Creech JR, Godin CS, et al. 1995. Chloroethylene mixtures Pharmacokinetic modeling and/n vitro metabolism of vinyl chloride, trichloroethylene, and tranv-l,2-dichloroethylene in rats. Toxicol Appl Pharmacol 130 237-247. 

Castro CE, DM Riebeth, NO Belser (1992a) Biodehalogenation the metabolism of vinyl chloride by Methylosinus trichosporium OB-3b. A sequential oxidative andreductive pathway through chloroethylene oxide. Environ Toxicol Chem 11 749-755. 

Castro CE, RS Wade, DM Riebeth, EW Bartnicki, NO Belser (1992b) Biodehalogenation rapid metabolism of vinyl chloride by a soil Pseudmonas sp. Direct hydrolysis of a vinyl C-Cl bond. Environ Toxicol Chem 11 757-764. 

Castro CE, NO Belser (1990) Biodehalogenation oxidative and reductive metabolism of 1,1,2-trichloroethane by Pseudomonas putida—biogeneration of vinyl chloride. Environ Toxicol Chem 9 707-714. 

Tetrachoroethylene (perchloroethylene, PCE) is the only chlorinated ethene that resists aerobic biodegradation. This compound can be dechlorinated to less- or nonchlorinated ethenes only under anaerobic conditions. This process, known as reductive dehalogenation, was initially thought to be a co-metabolic activity. Recently, however, it was shown that some bacteria species can use PCE as terminal electron acceptor in their basic metabolism i.e., they couple their growth with the reductive dechlorination of PCE.35 Reductive dehalogenation is a promising method for the remediation of PCE-contaminated sites, provided that the process is well controlled to prevent the buildup of even more toxic intermediates, such as the vinyl chloride, a proven carcinogen. 

Duverger M, Lambotte M, Malvoisin E, et al. 1981a. Metabolic activation and mutagenicity of 4 vinylic monomers (vinyl chloride, styrene, acrylonitrile, butadiene). Toxicol Eur Res 3 131-140. 

Significant activation occurs during the microbial metabolism of trichloroethylene (TCE). This compound was once widely used and now represents a major contaminant of many aquifers. Because TCE is metabolized by many bacteria, its elimination by bioremediation is being actively pursued. However, a major product frequently encountered is vinyl chloride, a potent carcinogen ... 

Unsaturated aliphatic compounds and heterocyclic compounds may also be metabolized via epoxide intermediates as shown in Figure 4.6 and chapter 5, Figure 14. Note that when the epoxide ring opens, the chlorine atom shifts to the adjacent carbon atom (Fig. 4.6). In the case of the furan ipomeanol and vinyl chloride, the epoxide intermediate is thought to be responsible for the toxicity (see below and chap. 7). Other examples of unsaturated aliphatic compounds, which may be toxic and are metabolized via epoxides, are diethylstilboestrol, allylisopropyl acetamide, which destroys cytochrome P-450, sedormid, and secobarbital. 

Aliphatic hydroxylation. As well as unsaturated aliphatic compounds such as vinyl chloride mentioned above, which are metabolized by epoxidation, saturated aliphatic compounds also undergo oxidation. The initial products will be primary and secondary alcohols. For example, the solvent n-hexane is known to be metabolized to the secondary alcohol hexan-2-ol and then further to hexane-2,5-dione (Fig. 4.9) in occupationally exposed humans. The latter metabolite is believed to be responsible for the neuropathy caused by the solvent. Other toxicologically important examples are the nephrotoxic petrol constituents, 2,2,4- and 2,3,4-trimethylpentane, which are hydroxylated to... 

There is also an enzyme for removal of methyl and ethyl groups from bases by oxidizing them to their respective aldehydes-the Aik B repair enzyme. Lipid epoxides, which may be produced in inflammatory tissue and can yield alkylated bases, will also be repaired by this enzyme (Fig. 6.47). Metabolic activation of vinyl chloride will also yield the same adduct (see chap. 7). 

Vinyl chloride is readily absorbed through skin and is rapidly eliminated, either unchanged or as metabolites. The metabolism is catalyzed by cytochromes P-450, and vinyl chloride induces its own metabolism but also destroys cytochrome P-450. The tumor incidence in rats correlates... 

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