Biotransformation xenobiotic substrates

The numerous biotransformations catalyzed by cytochrome P450 enzymes include aromatic and aliphatic hydroxylations, epoxidations of olefinic and aromatic structures, oxidations and oxidative dealkylations of heteroatoms and as well as some reductive reactions. Cytochromes P450 of higher animals may be classified into two broad categories depending on whether their substrates are primarily endogenous or xenobiotic substances. Thus, CYP enzymes of families 1-3 catalyze... 

Metabolic pathways containing dioxygenases in wild-type strains are usually related to detoxification processes upon conversion of aromatic xenobiotics to phenols and catechols, which are more readily excreted. Within such pathways, the intermediate chiral cis-diol is rearomatized by a dihydrodiol-dehydrogenase. While this mild route to catechols is also exploited synthetically [221], the chirality is lost. In the context of asymmetric synthesis, such further biotransformations have to be prevented, which was initially realized by using mutant strains deficient in enzymes responsible for the rearomatization. Today, several dioxygenases with complementary substrate profiles are available, as outlined in Table 9.6. Considering the delicate architecture of these enzyme complexes, recombinant whole-cell-mediated biotransformations are the only option for such conversions. E. coli is preferably used as host and fermentation protocols have been optimized [222,223]. 

These results may be viewed in the wider context of interactions between potential ligands of multifunctional xenobiotics and metal cations in aquatic environments and the subtle effects of the oxidation level of cations such as Fe. The Fe status of a bacterial culture has an important influence on synthesis of the redox systems of the cell since many of the electron transport proteins contain Fe. This is not generally evaluated systematically, although the degradation of tetrachloromethane by a strain of Pseudomonas sp. under denitrifying conditions clearly illustrated the adverse effect of Fe on the biotransformation of the substrate (Lewis and Crawford 1993 Tatara et al. 1993). This possibility should therefore be taken into account in the application of such organisms to bioremediation programs. 

One of the most intriguing and best explored specificities of hydrolases is their product enantiospecificity, a property that is not restricted to the biotransformation of xenobiotics since it is displayed by lipases acting on their physiological substrates. Indeed, prochiral triglycerides have been found to be hydrolyzed with marked product enantioselectivity by various lipases [51] [52], Such specificity can hardly be fortuitous and must have a physiological significance, which remains to be understood. 

This biotransformation is common to many xenobiotics and diminishes the potential toxicity of the substrate and facilitates its biliary and urinary elimination by increasing its hydrophilicity. Flavonoid metabolites are transported to extrahe-patic tissues and eventually to the kidneys, where they are excreted in the urine or incorporated into bile and excreted in feces.13 Because phase II metabolism is highly efficient with respect to the flavonoids, aglycones (except for anthocyanins)... 

Table 2 Examples of Clinically Relevant Substrates, Inhibitors, and Inducers of the Major Human Liver Microsomal P450 Enzymes Involved in Xenobiotic Biotransformation... 

The chemical modification of xenobiotics in the body is called biotransformation, metabolism, or metabolic clearance. Enzymes involved in metabolism are either membrane bound (e.g., endoplasmic reticulum and mitochondria) or freely soluble within the cytosol. Because these metabolic enzymes are not particularly substrate specific, they can metabolize compounds with fairly diverse chemical structures, including some endogenous compounds such as steroids, bile acids, and heme (endobiotics). 

The assay method described by Eaton and Stapleton (1989), measures the activities of both cytosolic glutathione 5-transferase and microsomal epoxide hydrolase toward benzo[a]pyrene-4,5-oxide as a substrate. These enzymes are important in the biotransformation of many epoxide xenobiotics, including potentially carcinogenic arene oxides. 

---