Dichloromethane is metabolized to CO and HCHO (carcinogen). The metabolites of trihalomethanes start with loss of halide (via P4502E1), leading to CO production. Covalent bonding to macromolecules occurs via phosgene in case of chloroform and via dibromocarbonyl in the case of bromoform. Chloroform is metabolized to reactive phosgene, and carbon tetrachloride forms tri-chloromethyl, trichloromethylperoxy, and chlorine-free radicals. Several haloalkanes are first conjugated with GSH in liver and then metabolized to cysteine conjugates in kidney. The latter conjugates are converted, by /3-lyase, to episulfonium ions.
Metabolism of haloethylenes (trichloroethylene, per-chloroethylene, vinyl chloride, vinyl bromide, vinyl fluoride, vinylidene chloride, vinylidene fluoride) starts with epoxidation (by P4502E1). Resulting oxiranes are highly reactive and bind covalently to nucleic acids. Chlorinated ethylene epoxides breakdown as a function of halogenated substituents on the carbon. Compared to ethylene oxide, vinyl chloride and vinylidene chloride with increasing chlorination show an increase in bond strength of the chlorinated carbon to the oxygen and a decrease in the bond strength to nonchlorinated carbon. When each carbon is substituted with single chlorine, the C-O bonds become equally stable. When there are two chlorines on one carbon and one on the other, there is, again, a weakening of the less chlorinated C-O bond. The asymmetrical chloroethylene is more carcinogenic than symmetrical ones because of the bond breakage, which potentiates covalent bonding to DNA. There are limits to the effectiveness of highly reactive species, for example, the weak carcinogenic activity of vinyl chloride may be due to the instability of its putative metabolite (1,1-dichloroxirane), which is likely to be degraded rapidly. The less reactive oxiranes bind to DNA more readily and stably. Trichloro- and tetrachloroethylenes are metabolized to monochloroacetic acid and trichloro-acetic acid, which are excreted as such or as their glucuronides and alcohols.
The environmental fate of most aromatic HHCs is determined by halogen substituents and the types of organisms exposed to them. The position of chlorination is more important than the degree of chlorination in biotransformation and degradation. Chlorination of biphenyls at ortho-position causes steric hindrance and decreases the degree of coplanarity at 2,29,6,69. Chlorinated dioxins and furans are held in coplanar orientation by the oxygen bridge. Aerobic bacterial degradation of PCBs involves dechlorination at o- and m-positions. In sediments, bacterial dechlorination is inversely proportional to their lipophilicity. In soils and sediments, biodegradation, hydrolysis, and photolysis determine their fate. The dechlorinated products can be attacked by bacterial deoxygenases as well as by animal P450 oxygenases.
Animal metabolism of polychlorinated aromatics starts with attack by P450 monooxygenases causing hydroxyla-tion (addition plus keto-enol rearrangement) via epoxidation, with or without displacement of the chlorine (NIH shift). Vinyl halogens favor epoxidation. PCBs with 4,4' and/or 3,3',5,5'-chlorination are refractory to biotransformation, while PCBs with four or more chlorines but with hydrogen in either 4 and/or in 4,59-positions of one or both rings are readily metabolized. Polyhalogenated aromatics induce P450 monoxygenases; coplanar PCBs and TCDD induce P4501A1 while noncoplanars induce P4502B isozymic forms. P4501A1 can oxidize coplanar
PCBs readily while P4502B preferentially oxidizes o-sub-stituted congeners. Resulting hydroxylated metabolites can be conjugated with glucuronic acid and/or glutathione, which are excreted in bile; but glutathione conjugates are re-absorbed or metabolized to meracaptans, which are excreted as mercapturic acid or form corresponding sulf-hydryl and methylated products. The methyl-thio-PCB can be further oxidized to corresponding sulfoxides and sulfones, which may be retained in tissues. The methylsul-fonyl metabolites of PCBs, HCB, and DDT show high tissue-specific binding and toxic effects. Similar hydroxy-lations and dechlorinations and/or NIH shifts occur in dioxins and furans. The dihydroxy products following /-oxidation can also lead to ring opening and reduction of furans, which reduces their toxicity.
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