Enzymatic metabolism, xenobiotics

The likelihood that a xenobiotic species will undergo enzymatic metabolism in the body depends on the chemical nature of the species. Compounds with a high degree of polarity, such as relatively ionizable carboxylic acids, are less likely to enter the body system and, when they do, tend to be quickly excreted. Therefore, such compounds are unavailable, or available for only a short time, for enzymatic metabolism. Volatile compounds, such as dichloromethane or diethylether, are... 

An inhibiting chemical slows the enzymatic metabolism of a toxic chemical. In this instance, if the uptaken chemical itself is the toxin, inhibition will slow the metabolism and intensify its action. If the metabolite of the absorbed xenobiotic is the toxic agent, inhibition will decrease the toxic affect. Vinyl chloride uptake in rats results in the lowering of cytochrome P450 and a corresponding loss of ability to metabolize other xenobiotics. Other inhibitors include diethyl maleate, which inhibits glutathione s-transferase and 1-aminobenzotriazole, which inhibits P450. 

To understand the concept of the metabolism, an elaboration of the "elimination" process (i.e., biotransformation and excretion) is necessary. Molecules circulating in the blood may undergo one of three distinct fates, which will contribute to the elimination of a given xenobiotic compound excretion unchanged, non-enzymatic chemical transformation, and enzymatic metabolism. 

Most living beings have the capacity to metabolize xenobiotics by the process denominated biotransformation (Tuvikene, 1995). Biotransformation is characterized as a conjunct of enzymatic reactions, responsible for the conversion of the liposoluble substances in hydrosoluble facilitating, thus, their excretion process. However, although the purpose of the xenobiotics biotransformation is detoxification not always the originated metabohte is less toxic than the own chemical. Thus, xenobiotics biotransformation can increase the toxicity of the chemical products by the formation of electrophilic metabolites, extremely reactive, which can present potential to bind, covalently, with macromolecules inside the cells with DNA, RNA and proteins, which can result in several alterations such as disturbance in the immime system, mutations and even the organism death (Stanley, 1992,1994 Landis and Yu, 1998 Guecheva and Henriques, 2003). 

Enzyme levels and activities within the human population can vary considerably and many of the enzymes involved in the metabolism of xenobiotics are polymorphicaUy distributed in the human population. Genetic polymorphism (from Greek poly many , morph form ) is defined as the occurrence of at least two different alleles, with allele frequencies exceeding 1% at a particular locus. The allelic variants include point mutations as well as deletions and insertions and genetic polymorphism may cause an increase, a decrease, or no change in enzymatic activity. 

Enzymatic catalysis of reactions. Important enzymes are located in membranes at the interface between the lipid and aqueous phases. This is where reactions with apolar substrates occur. Examples include lipid biosynthesis (see p. 170) and the metabolism of apolar xenobiotics (see p. 316). The most important reactions in energy conversion—i.e., oxidative phosphorylation (see... 

Reactive metabolites of xenobiotics may differ in reactivity, and therefore have varying impact on enzymatic activities in terms of proximity to their origin. For example, some intermediates are highly reactive and directly inhibit the enzyme that leads to their formation. These substances are commonly referred to as suicide inhibitors, for obvious reasons. Some suicide inhibitors, such as piperonyl butoxide (PBO), a pesticide synergist) are common inhibitors of certain CYP isozymes. PBO amplifies the toxicity of certain insecticides by inhibiting the insect s CYP enzymes that are involved in its degradation. It is metabolized to a highly reactive carbene, which forms an inhibitor complex with the heme iron of CYP, as shown in Scheme 3.6. 

The enzymatic route which a drug or poison follows in its metabolism is very specific to the xenobiotic itself. Substances with the same type of structures need not go through the same pathway. And the "active" form of the drug or the "toxic" form of the poison may occur either at the beginning or during the course of transformation. Usually synthetic combinations are not active or toxic but many of their precursors are. The following diagram illustrates the possibilities of a biotransformation process. 

Other enzymatic activities which are present in the cells, e.g. transferases, hydrolases, etc. which may also serve to metabolize the xenobiotic. In addition, the level of endogenous OR should be adequate for P450 catalytic activity. OR appears to be expressed in virtually all mammalian cell lines, however the levels can vary substantially (Sawada et al., 1991). Alternatively, OR coexpression can be performed. 

Hodgson E. Chemical and environmental factors affecting metabolism of xenobiotics. In Hodgson E, Levi PE, eds. Introduction to Biochemical Toxicology. 2nd ed. Connecticut Appleton-Lange, 1994. Jakoby WE, ed. Enzymatic Basis of Detoxication. New York Academic Press, 1980. 

In such a case, the organisms have an enzyme capable of oxidizing Q. Only degradation of Q allows the bacteria to obtain carbon and energy sufficient to maintain and multiply the population. Due to imperfect substrate specificity, the same enzymatic reaction takes place with BQ too. Similar co-metabolism by enzymes intended for natural substrates has been reported for many xenobiotic compounds like chlorinated solvents (Semprini, 1997), chlorophenols (Kim and Hao, 1999), and chlorobiphenyls (Kohler et al., 1988). 

In vitro Metabolism. Numerous variables simultaneously modulate the in vivo metabolism of xenobiotics therefore their relative importance cannot be studied easily. This problem is alleviated to some extent by in vitro studies of the underlying enzymatic mechanisms responsible for qualitative and quantitative species differences. Quantitative differences may be related directly to the absolute amount of active enzyme present and the affinity and specificity of the enzyme toward the substrate in question. Because many other factors alter enzymatic rates in vitro, caution must be exercised in interpreting data in terms of species variation. In particular, enzymes are often sensitive to the experimental conditions used in their preparation. Because this sensitivity varies from one enzyme to another, their relative effectiveness for a particular reaction can be sometimes miscalculated. 

Biotransformation refers to changes in xenobiotic compounds as a result of enzyme action. Reactions not mediated by enzymes may also be important. As examples of nonenzymatic transformations, some xenobiotic compounds bond with endogenous biochemical species without an enzyme catalyst, undergo hydrolysis in body fluid media, or undergo oxidation-reduction processes. However, the metabolic phase I and phase II reactions of xenobiotics discussed here are enzymatic. 

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