Xenobiotic metabolizing enzymes substrates

A new tool for computational ADME/Tox called MetaDrug includes a manually annotated Oracle database of human drug metabolism information including xenobiotic reactions, enzyme substrates, and enzyme inhibitors with kinetic data. The MetaDrug database has been used to predict some of the major metabolic pathways and identify the involvement of P450s [78]. This database has enabled the generation of over 80 key metabolic... 

Xenobiotic-metabolizing enzymes commonly exist in multiple forms (e.g., glutathione 5-transferases and P450s). These isozymes are all relatively nonspecific but differ from one another in the relative affinities of the different substrates. 

Because exogenous chemicals can be inducers and/or inhibitors of the xenobiotic-metabolizing enzymes of which they are substrates such chemicals may interact to bring about toxic sequelae different from those that might be expected from any of them administered alone. 

TABLE 10.1. Phase I Xenobiotic-Metabolizing Enzymes with Examples of Substrates... 

There are several examples of activation of xenobiotic-metabolizing enzymes by compounds other than the substrate. This differs from induction (described in Chapter 9) in that it is an immediate effect on a preexisting enzyme, occurring in an enzyme preparation in vitro, that does not involve de novo protein synthesis. The occurrence and significance of such stimulation in vivo is not apparent. 

As with the mixed-function oxidases involved in xenobiotic metabolism, the substrate specificity of the steroid hydroxylases is dictated, in part, by the existence of multiple forms of both microsomal and mitochondrial cytochrome P-450s and further opportunities for specificity are provided by the distinct localization of the various enzymes in either the mitochondria or the endoplasmic reticulum. 

There are two distinct types of epoxide hydrolases, both widely distributed in mammalian tissues. One type is localized primarily in the endoplasmic reticulum, the second in the cytosol. The microsomal and cytosolic enzymes have different properties, including substrate selectivities. Several inducers of xenobiotic metabolizing enzymes, including pheno-barbital, planar PCB congeners, and ra s-stilbene oxide, selectively increase (induce) microsomal, but not cytosolic, epoxide hydrolase activity. 

In addition to the physicochemical factors that affect xenobiotic metabolism, stereochemical factors play an important role in the biotransformation of drugs. This involvement is not unexpected, because the xenobiotic-metabolizing enzymes also are the same enzymes that metabolize certain endogenous substrates, which for the most part are chiral molecules. Most of these enzymes show stereoselectivity but not stereospecificity in other words, one stereoisomer enters into biotransformation pathways preferentially but not exclusively. Metabolic stereochemical reactions can be categorized as follows substrate stereoselectivity, in which two enantiomers of a chiral substrate are metabolized at different rates product stereoselectivity, in which a new chiral center is created in a symmetric molecule and one enantiomer is metabolized preferentially and substrate-product stereoelectivity, in which a new chiral center of a chiral molecule is metabolized preferentially to one of two possible diastereomers (87). An example of substrate stereoselectivity is the preferred decarboxylation of S-a-methyIdopa to S-a-methyIdopamine, with almost no reaction for R-a-methyIdopa. The reduction of ketones to stereoisomeric... 

Both xenobiotics and endogenous substrates are primarily metabolized by a super-family of enzymes, named cytochrome F450s (CYP450s,... 

Ex vivo systems derived from animals and from human organs can be used to investigate the in vitro metabolism of xenobiotics. Cell lines, which are transfected to express species-specific metabolic enzymes, can also be used to identify the enzymes involved in the metabolism of a specific substance. Blocking the metabolism by an enzyme specific substrate or by antibodies is also helpful for the identification of the enzymes involved in the metabolism of a substance. 

There are five forms of the enzyme, but only two, the microsomal and soluble forms are important in xenobiotic metabolism. These two forms have different substrate specificities. The microsomal form is located in the endoplasmic reticulum in close proximity to cytochromes P-450, and like the latter is also present in greater amounts in the centrilobular... 

Generally the enzymes involved in xenobiotic metabolism are less specific than the enzymes involved in intermediary, endogenous substrate metabolism. 

The level of a particular enzyme involved in xenobiotic metabolism can obviously affect the extent of metabolism by that enzyme. Again, competition may play a part if endogenous and exogenous substrates are both metabolized by an enzyme, as is the case with some of the forms of cytochromes P-450, which metabolize steroids, or NADPH cytochrome P-450 reductase and cytochrome b5 reductase, which are also involved in heme catabolism and fatty acid metabolism, respectively. 

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