Metabolism dehalogenation

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

Chlorobenzoates may be formed during the initial steps in the aerobic degradation of PCBs, and their further metabolism illustrates a number of pathways. There are several reactions that carry out dehalogenation including dioxygenation, hydrolysis, and reduction. 

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. 

More recently [135], 72 and 73 were also found in the sea hare Stylocheilus longicauda but, surprisingly, only dehalogenated 73 was present in the algal food source, Lyngbya majuscula. This metabolic comparison suggested an uncommon in vivo bromination of 73, but further experiments need to ascertain whether L. majuscula is the unique food source of S. longicauda. 

The metabolism of carbon tetrachloride proceeds via cytochrome P-450-dependent dehalogenation (Sipes et al. 1977). The first step involves cleavage of one carbon-chlorine bond to yield Cl- and a trichloromethyl free radical, which is then oxidized to the unstable intermediate trichloromethanol, the precursor of phosgene. Hydrolytic dechlorination of phosgene yields C02 and HC1 (Shah et al. 1979). Although there are similarities in the metabolism of chloroform and carbon tetrachloride, metabolic activation of chloroform produces primarily phosgene, whereas the level of phosgene production from... 

Many different pathways, mechanisms, and enzymes are associated with activation. These include dehalogenation, AT-nitrosation of secondary amines, epoxidation, conversion of phosphothionates to phosphate, metabolism of phen-oxyalkanoic acids, oxidation of thioethers, hydrolysis of esters and peroxides. The following is a summary. 

Halogenated aliphatics can be partially or completely degraded under anaerobic conditions through a transformation reaction called reductive de-halogenation. Often a co-metabolic degradation step, reductive dehalogenation... 

Another type of dehalogenation occurs in xenobiotic metabolism, namely halide elimination with cyclization. These intramolecular nucleophilic substitutions are discussed in Sect. 11.4.2 (nitrogen mustards) and 11.8. 

The metabolism of 1,2,3-trichloropropane (11.27), an industrial solvent that undergoes biotransformation via dechlorination at C(l) and C(2) [60], is a clearer case of oxidative dehalogenation. Following incubation with human or rat liver microsomes, the compound was converted to 1,3-dichloroacetone (11.29), which could a priori be produced by oxidative dehalogenation (i. e., via 11.28) or by hydrolytic dehalogenation. In this study, evidence was found... 

Oxidative dehalogenation. Halogen atoms may be removed from xenobiotics in an oxidative reaction catalyzed by cytochromes P-450. For example, the anesthetic halothane is metabolized to trifluoroacetic acid via several steps, which involves the insertion of an oxygen atom and the loss of chlorine and bromine (Fig. 4.28). This is the major metabolic pathway in man and is believed to be involved in the hepatotoxicity of the drug. Trifluoroacetyl chloride is thought to be the reactive intermediate (see chap. 7). 

Peak plasma concentration of meclofenamate occur 0.5 to 1 h after oral administration. The binding to plasma proteins is over 99% and the plasma elimination half-life is about 2 to 4 h. Meclofenamate is metabolized by oxidation, hydroxylation, dehalogenation, and glucuronidation. Metabolites are excreted mainly in the urine with about 20 to 30% being excreted in the faeces (Koup et al., 1990). A 3-hydroxymethyl metabolite of meclofenamate has been reported to be active. 

Chloro- -triazines have been shown to be metabolized in plants by one of four competing processes hydrolytic dehalogenation, oxidative /V-dcalkylation, nucleophilic displacement of the chlorine atom with glutathione, and ami-nation or deamination reactions. Much of the early research focused on the first three processes and attempted to determine the relative importance of each process to herbicide tolerance. The relevant research undertaken between 1961 and 1973 will be discussed. 

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