Metabolism of xenobiotics

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... 

Microsomes are widely used to study the metabolism of xenobiotics. Enzymes can be chararacterized on the basis of their requirement for cofactors (e.g., NADPH, UDPGA), and their response to inhibitors. Kinetic studies can be carried out, and kinetic constants determined. They are very useful in studies of comparative metabolism, where many species not available for in vivo experiment can be compared with widely investigated laboratory species such as rats, mice, feral pigeon, Japanese quail, and rainbow trout. 

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. 

Button WG, Judson PN, Long A, Vessey JD. Using absolute and relative reasoning in the prediction of the potential metabolism of xenobiotics. J Chem Inf Comput Sci 2003 43 1371-7. 

In mammals, peptide hormones typically contain only the a-amino acids of proteins finked by standard peptide bonds. Other peptides may, however, contain nonprotein amino acids, derivatives of the protein amino acids, or amino acids finked by an atypical peptide bond. For example, the amino terminal glutamate of glutathione, which participates in protein folding and in the metabolism of xenobiotics (Chapter 53), is finked to cysteine by a non-a peptide bond (Figure 3—3). The amino terminal glutamate of thyrotropin-... 

Section VI consists of discussions of eleven special topics nutrition, digestion, and absorption vitamins and minerals intracellular traffic and sorting of proteins glycoproteins the extracellular matrix muscle and the cy-toskeleton plasma proteins and immunoglobulins hemostasis and thrombosis red and white blood cells the metabolism of xenobiotics and the Human Genome Project. 

The metabolism of xenobiotics by both terrestrial and sediment-dwelling biota has been studied, and provides illustrations of the importance of uptake by food or by sorbed sediment. Some examples of metabolism by terrestrial biota include the following. 

Sandermann H (1994) Higher plant metabolism of xenobiotics the green liver concept. Pharmacogenetics 4 225-241. 

This is important not only in field investigations. Even in laboratory experiments on the metabolism of xenobiotics, problems of association between the substrate and the microbial cells may occur. If this were not quantitatively evaluated or eliminated, the results and interpretation of such experiments would be seriously compromised. 

Consistent with the preceding comments on the metabolism of xenobiotics in the presence of additional carbon substrates, the result of deliberate addition of organic carbon may be quite complex and will not be addressed in detail. Two examples on rates of mineralization are given as illustration in which addition of glucose apparently elicited two different responses. It should, however, be emphasized that since the concentration of readily degradable substrates in natural aquatic systems will generally be extremely low, the environmental relevance of such observations will inevitably be restricted ... 

Although application of 0 has been less frequent, it has been used effectively to determine the source of oxygen and the number of oxygen atoms incorporated during metabolism of xenobiotics under both aerobic and anaerobic conditions. Some typical examples are given below ... 

The metabolism of xenobiotics by other plants including aqnatic plants has been examined ... 

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. 

Abourashed, E.A., Clark, A.M. and Hufford, C.D. (1999) Microbial models of mammalian metabolism of xenobiotics an updated review. Current Medicinal Chemistry, 6, 359-374. 

Korzekwa KR, Jones JP. Predicting the cytochrome P450 mediated metabolism of xenobiotics. 

In Vitro Metabolic Activation. The target cells for in vitro mutagenicity tests often possess a limited (often overlooked) capacity for endogenous metabolism of xenobiotics. However, to simulate the complexity of metabolic events that occur in the whole animal, there is a critical need to supplement this activity. 

Smith, G., Watkins, J., Thompson, T., Rozman, K. and Klassen, C. (1984). Oxidative and conjugative metabolism of xenobiotics by livers of cattle, sheep, swine and rats. J. Anim. Sci. 58 386-395. 

Comparative Metabolism. Since the liver is the major organ involved in the biotransformation of xenobiotics, primary hepatocyte cultures provide an excellent model for in vitro metabolism studies. Primary hepatocyte cultures provide useful tools with which to study the comparative metabolism of xenobiotics by both humans and laboratory animals. 

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]. 

Reflecting the increasing importance of drug transporters in pharmacokinetics, we need to extend the historical two-phase concept for the metabolism of xenobiotics. As shown in Figure 15.1, the metabolic phases I (oxidation) and II (conjugation) are flanked by drug transporter phases 0 (uptake) and III (export). Phase 0 is the first step... 

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