Oxidative metabolism of xenobiotic

Lang D, Kalgutkar AS (2003) Non-P450 mediated oxidative metabolism of xenobiotics. In Lee JS, Obach RS, Fisher MB (eds) Drug Metabolizing Enzymes. Marcel Dekker, New York, pp 483-539... 

Strolin-Benedetti, M., Whomsley, R., and Baltes, E. Involvement of enzymes other than CYPs in the oxidative metabolism of xenobiotics. Expert Opin. Drug Metab. Toxicol. 2,895-921, 2006. 

The generation of potentially toxic, reactive iminium ions from the oxidative metabolism of xenobiotic N-alkyl compounds. Biochem Pharmacol 34(12) 2055-2061, 1985. 

The CYPs are present in the liver the greatest concentration is in the smooth endoplasmic reticulum of the centrilobular hepatocytes. They are also present in many other tissues, including the gastrointestinal tract. CYPs are capable of reacting with multiple endogenous and exogenous compounds, and they are active in bilirubin metabolism, cholesterol synthesis, hormone synthesis and catabolism, and vitamin D metabolism. They are of particular interest because of their role in the oxidative metabolism of xenobiotics as part of phase I reactions and the biotransformation of lipophilic compounds to more polar compounds, which are readily excreted by the kidney into the urine. 

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... 

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. 

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... 

Metabolism - a final factor in need of comparative studies is the metabolism of xenobiotics. One obvious difference between mammalian and fish species is that their bodies usually function at temperatures at least 10°C different. This fact undoubtedly explains some differences in metabolic rate but even when in vitro incubations are run at optimal temperatures there is a 10 - 100 fold higher rate of mammalian vs. fish metabolism (14, 15). In other words, the level of the xenobiotic-metabolizing capacity, especially for oxidative pathways, of the poikilothermic animals is considerably lower than that of the homeothermic species. Elsewhere in this volume Dr. Bend has focused on this aspect of the handling of xenobiotics by fish (16). 

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. 

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