Conjugation biotransformations

Another variation in GSH conjugate biotransformation has been observed in metabolism of preMAP metabolites of naphthalene (11). 

The metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reactions, classically referred to as phases one and two. Phase I is a functionalization of the lipophilic compound that can be used to attach a conjugate in Phase II. The conjugated product is usually sufficiently water-soluble to be excretable into the urine. The most important biotransformations of Phase I are aromatic and aliphatic hydroxylations catalyzed by cytochromes P450. Other Phase I enzymes are for example epoxide hydrolases or carboxylesterases. Typical Phase II enzymes are UDP-glucuronosyltrans-ferases, sulfotransferases, N-acetyltransferases and methyltransferases e.g. thiopurin S-methyltransferase. 

FIGURE 2.14 Phase 2 biotransformation—conjugation. (1) Glucuronide formation. (2) Sulfate formation. (3) Glutathione conjugation. 

Residues of PCBs in animal tissues include not only the original congeners themselves, but also hydroxy metabolites that bind to cellular proteins, for example, transthyretin (TTR Klasson-Wehler et al. 1992 Brouwer et al. 1990 Fans et al. 1993). Small residues are also found of methyl-sulfonyl metabolites of certain PCBs (Bakke et al. 1982, 1983). These appear to originate from the formation of glutathione conjugates of primary epoxide metabolites, thus providing further evidence of the existence of epoxide intermediates. Further biotransformation, including methylation, yields methyl-sulfonyl products that are relatively nonpolar and persistent. 

A number of biotransformations have been accomplished by rhodococci, including, for example, the hydrolysis of nitriles including polyacronitriles (Tauber et al. 2000), and the reduction of the conjugated C=C double bond in 2-nitro-l-phenylprop-l-ene (Sakai et al. 1985). 

Microbial oxidation of drug substrates occurs in a similar fashion to mammalian oxidative biotransformation. In contrast, microbial cultures rarely catalyze conjugations comparable to those in mammalian system (glucuronidation, sulfation and GSH conjugation). It is thus not surprising that microbial bioreactors are mainly used in the synthesis of oxidative metabolites. 

Both enzymatic and nonenzymatic biotransformation of acrylonitrile occurs. Acrylonitrile is capable of covalently binding to proteins and other macromolecules such as lipids or nucleic acids, or acrylonitrile can also be directly conjugated to glutathione and excreted in urine as cyanoethylmercapturic acid. 

Biotransformation of PCP in mammals occurs via conjugation, reductive dechlorination, hydrolytic dechlorination, and oxidation. In the process, a number of metabolites are formed, some of which are demonstrably toxic (Renner and Hopfer 1990 Jansson and Jansson 1991 Reigner et al. 1991). Metabolites of PCP found in rat urine and identified (acute oral LD50 to mice, in mg/kg BW) include (Renner and Hopfer 1990) ... 

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