Xenobiotics biotransformation reactions

A second area of drug discovery and development in which enzyme reactions play a critical role is in the study of drug metabolism and pharmacokinetics. The elimination of xenobiotics, including drug molecules, from systemic circulation is driven by metabolic transformations that are entirely catalyzed by enzymes. Table 1.2 lists some of the enzyme-catalyzed transformations of xenobiotics that commonly contribute to drug molecule elimination. These biotransformation reactions... 

In general, biotransformation reactions are beneficial in that they facilitate the elimination of xenobiotics from pulmonary tissues. Sometimes, however, the enzymes convert a harmless substance into a reactive form. For example, CYP-mediated oxidation often results in the generation of more reactive intermediates. Thus, many compounds that elicit toxic injury to the lung are not intrinsically pneumotoxic but cause damage to target cells following metabolic activation. A classic example of this is the activation of benzo(a)pyrene, which is a constituent of tobacco smoke and combustion products, and is... 

One xenobiotic can affect the toxicity of another by either increasing enzyme activity or depleting essential cofactors. Many of the enzymes involved in biotransformation reactions are inducible, such that... 

Biotransformation reactions of the original xenobiotic may result in compounds with fundamentally different physical properties and toxicities. The apparently ubiquitous distribution of haloge-nated anisoles (Wittlinger and Ballschmiter 1990 Fiihrer and Ballschmiter 1998) attests to the importance of O-methylation reactions that are discussed in Section 6.11.4. 

An additional feature of using microbes to metabolize compounds—be they natural or synthetic—is that many of the biotransformation reactions carried out by microbes are the same as those carried out in humans and animals on xenobiotic... 

In addition to the failures of biotransformation reactions to promote the elimination of some xenobiotics. Phase I reactions occasionally have the effect of increasing rather than reducing a chemical s toxicity. For example, several enzymes in the cytochrome P-450 family are known to convert foreign chemicals into electrophiles. Electrophiles are molecules that are deficient in electrons as such, they tend to react with molecules that are relatively electron-rich such as proteins, lipids, and DNA, which are essential to the health of cells. When a cellular molecule is attacked by an electrophile, its structure is altered, and its function is undermined (Chapter 7). 

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). 

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. 

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... 

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