Metabolism of xenobiotic compounds

Pseudomonads also have the ability for xenobiotic metabolism and are capable of carrying out diverse sets of chemical reactions. Pseudomonas species is used in the commercial production of acrylamide (qv) (18). Several operons involved in the metabolism of xenobiotic compounds have been studied. Use of Pseudomonads for the clean up of the environment and for the production of novel chemical intermediates is likely to be an area of active research in the 1990s. 

Foth, H. Role of the lung in accumulation and metabolism of xenobiotic compounds-implications for chemically induced toxicity. Crit. Rev. Toxicol. 25 165-205, 1995. 

The types of enzymes that bring about hydrolysis are hydrolase enzymes. Like most enzymes involved in the metabolism of xenobiotic compounds, hydrolase enzymes occur prominently in the liver. They also occur in tissue lining the intestines, nervous tissue, blood plasma, the kidney, and muscle tissue. Enzymes that enable the hydrolysis of esters are called esterases, and those that hydrolyze amides are amidases. Aromatic esters are hydrolyzed by the action of aryl esterases and alkyl esters by aliphatic esterases. Hydrolysis products of xenobiotic compounds may be either more or less toxic than the parent compounds. 

Figure 11.28 (a) Six compounds and their metabolites chosen as specific probes for activity of six CYP450 isozymes mainiy responsible for metabolism of xenobiotic compounds, (b) An example of the ESI-MS and ESI-MS/MS spectra used to select MRM transitions used in the LC-MS/MS assays for inhibition/induction of a specific isozyme, (c) HPLC-MRM chromatograms for the internal standard (propronanol) and for the metabolites of the six probe compounds obtained for a microsomal incubation. Reproduced from Peng, Rapid Commun. Mass Spectrom. 17, 509 (2003), with permission of John Wiley Sons Ltd. 

Wachett LP, Gibson DT. Metabolism of xenobiotic compounds by eiuymcs in cell extracts of the fungus Cunmnighatnella degans. Biochem J 1982 205 117-122. 

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 metabolism of foreign compounds (xenobiotics) often takes place in two consecutive reaction, classically referred to as phases one and two. Phase I is a... 

Two important examples of reductive metabolism of xenobiotics are the reductive dehalogenation of organohalogen compounds, and the reduction of nitroaromatic compounds. Examples of each are shown in Figure 2.13. Both types of reaction can take place in hepatic microsomal preparations at low oxygen tensions. Cytochrome P450 can catalyze both types of reduction. If a substrate is bound to P450 in the... 

Details of some inducible P450 forms that play key roles in the metabolism of xenobiotics are shown in Table 2.4. P450s belonging to family lA are induced by various lipophilic planar compounds including PAHs, coplanar PCBs, TCDD and other dioxins, and beta naphthoflavone (Monod 1997). As noted earlier, such planar compounds are also substrates for P450 lA. In many cases, the compounds induce the enzymes that will catalyze their own metabolism. Exceptions are refractory compounds such as 2,3,7,8-TCDD, which is a powerful inducer for P450 lA but a poor substrate. 

Phenols also constitute a major source of xenobiotic exposure to the body in the form of drugs and environmental pollutants. Oxidative metabolism of these compounds can lead to physiological damage, therefore the metabolism of these compounds is of great interest. LCEC has been a powerful tool for investigating the metabolism of aromatic compounds by the cytochrome P-450 system LCEC... 

T. E. Gram, The metabolism of xenobiotics by the mammalian lung, in Extrahepatic Metabolism of Drugs and Other Foreign Compounds (T. E. Gram, Ed.), S.P. Medical and Scientific Books, New York, 1980, pp. 159-209. 

The primary metabolism of an organic compound uses a substrate as a source of carbon and energy. For the microorganism, this substrate serves as an electron donor, which results in the growth of the microbial cell. The application of co-metabolism for bioremediation of a xenobiotic is necessary because the compound cannot serve as a source of carbon and energy due to the nature of the molecular structure, which does not induce the required catabolic enzymes. Co-metabolism has been defined as the metabolism of a compound that does not serve as a source of carbon and energy or as an essential nutrient, and can be achieved only in the presence of a primary (enzyme-inducing) substrate. 

The CYP family is composed of a large group of monooxygenases that mediate the metabolism of xenobiotics and endogenous compounds. If a drug is to be orally active, it should be both chemically and metabolically stable. Metabolism normally only takes place at a specific position of a molecular skeleton and, unfortunately, metabolic regularities are exceptions. Experienced chemists also find it very difficult to predict where metabolism occurs in a molecule [1]. 

Intestinal Metabolism Intestinal drug metabolism can occur by microflora present in the gut lumen, as well as by enzymes present in luminal fluids and in the intestinal mucosa [166], Metabolism of xenobiotics by gut microflora is low in comparison to metabolism by the gut mucosa and liver [62], However, the intestinal microflora (e.g., Bacteroides and Bifidobacteria) may play an important role in the first-pass metabolism of compounds that are poorly or incompletely absorbed by the gut mucosa, especially in the lower parts of the intestine. This bacterial metabolism is largely degradative,... 

Sipes IG, Wiersma DA, Armstrong DJ. 1986a. The role of glutathione in the toxicity of xenobiotic compounds Metabolic activation of 1,2-dibromoethane by glutathione. Adv Exp Med Biol 197 457-467. 

The existence of pathways for the in vivo catabolism of MAP metabolites to compounds that require further metabolism before the xenobiotic moiety is excreted from the body indicates that metabolism of xenobiotics by the MAP may, in some cases, represent only a transient detoxication. The thiols and methylated thiols that are formed represent new xenobiotics. 

The metabolism of foreign compounds is catalyzed by enzymes, some of which are specific for the metabolism of xenobiotics. The metabolic pathways involved may be many and various but the major determinants of which transformations take place are... 

Various sulfur-containing compounds, including thioamides, thioureas, thiols, thioethers and disulfides, are oxidized by this enzyme system. However, unlike cytochromes P-450, it cannot catalyze hydroxylation reactions at carbon atoms. It is clear that this enzyme system has an important role in the metabolism of xenobiotics, and examples will appear in the following pages. Just as with the cytochromes P-450 system, there appear to be a number of isoenzymes, which exist in different tissues, which have overlapping substrate specificities. 

But it is important to appreciate that the metabolism of foreign compounds is not completely separate from intermediary metabolism, but linked to it. Consequently, this will exert a controlling influence on the metabolism of foreign compounds. Some of the important factors controlling xenobiotic metabolism are... 

The first important metabolic approach used by microorganisms to initiate transformations of xenobiotic compounds involves hydrolyses. This set of reactions can occur under all environmental conditions. Also the enzymes that catalyze these degradation reactions are typically constitutive (i.e., always present), although their activity levels can be regulated (e.g., hydrolytic dehalogenases, Janssen et al., 2001). 

Now we consider situations in which transformation of the organic compound of interest does not cause growth of the microbial population. This may apply in many engineered laboratory and field situations (e.g., Semprini, 1997 Kim and Hao, 1999 Rittmann and McCarty, 2001). The rate of chemical removal in such cases may be controlled by the speed with which an enzyme catalyzes the chemical s structural change (e.g., steps 2, 3 and 4 in Fig. 17.1). This situation has been referred to as co-metabolism, when the relevant enzyme, intended to catalyze transformations of natural substances, also catalyzes the degradation of xenobiotic compounds due to its imperfect substrate specificity (Horvath, 1972 Alexander, 1981). Although the term, co-metabolism, may be used too broadly (Wackett, 1996), in this section we only consider instances in which enzyme-compound interactions limit the overall substrate s removal. Since enzyme-mediated kinetics were characterized long ago by Michaelis and Menten (Nelson and Cox, 2000), we will refer to such situations as Michaelis-Menten cases. 

In the selection of a microbial system and bioremediation method, some examination of the degradation pathway is necessary. At a minimum, the final degradation products must be tested for toxicity and other regulatory demands for closure. Recent advances in the study of microbial metabolism of xenobiotics have identified potentially toxic intermediate products (Singleton, 1994). A regulatory agency sets treatment objectives for site remediation, and process analysis must determine whether bioremediation can meet these site objectives. Specific treatment objectives for some individual compounds have been established. In other cases total petroleum hydrocarbons total benzene, toluene, ethyl benzene, and xylene (BTEX) or total polynuclear aromatics objectives are set, while in yet others, a toxicology risk assessment must be performed. 

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