Cytochrome P450 monooxygenases metabolism

Circulating melatonin is metabolized mainly in the liver, where it is first hydroxylated in the C6-position by cytochrome P450 monooxygenases (isoenzymes... 

Fig. 22.3 Cytochrome P450 monooxygenases and nicotine metabolism. An alignment of the amino acid sequences of the enzymes 2A6 and 2D6. Occurrences of the same amino acid residue at the same position are shown in black. Putative substrate recognition sites (SRS1—...

Hickman, D., Wang, J.P., Wang, Y. and Unadkat, J.D. (1998) Evaluation of the selectivity of in vitro probes and suitability of organic solvents for the measurement of human cytochrome P450 monooxygenase activities. Drug Metabolism and Disposition, 26 (3), 207-215. 

Whereas most, if not all, of the enzymes involved in xenobiotic metabolism can form reactive metabolites (Table 8.1), the enzyme systems most frequently involved in the activation of xenobiotics are those which catalyze oxidation reactions. The cytochrome P450 monooxygenases (CYP) are by far the most important enzymes involved in the oxidation of xenobiotics. This is because of the abundance of CYP (especially in the liver), the numerous isozymes of CYP, and the ability of CYP to be induced by xenobiotic compounds. 

The induction of liver enzymes has been demonstrated in many species, including humans, and probably represents a homeostatic, defense mechanism. Induction usually requires multiple exposures to the inducing agent over a period of several days, the time required for the synthesis of new protein. Enzymes induced include the cytochrome P450 monooxygenase system glucuronyltransferase the microsomal ethanol oxidative system and the steroid-metabolizing system. 

Fourth, certain segments of the nephron have a capacity for metabolic bioactivation. For example, the proximal and distal tubules contain isozymes of the cytochrome P450 monooxygenase system that may mediate intrarenal bioactivation of several protoxicants. Additionally, prostaglandin synthetase activity in medullary and papillary interstitial cells may be involved in cooxidation of protoxicants, resulting in selective papillary injury. 

Among the reactions performed by the cytochrome P450 monooxygenase system, epox-idation, hydroxylation, N-dealkylation, O-dealkylation, desulfuration, and sulfoxidation are the most important with respect to pesticide metabolism ... 

The metabolic pathways of diazinon are shown in Figure 8.26. Diazinon is mainly hydrolyzed to diethylthiophosphoric acid by cytochrome P450 monooxygenases and esterase (phosphatase). Diazinon is also oxidized by P450s to diazoxon. Microsomal monooxygenases also oxidize diazinon at the isopropyl group. The methyl group on the pyrimidine... 

The metabolic pathways of hydroprene will be used to illustrate the fate of juvenoid insecticides (Figure 8.31). It can be seen that the metabolism of hydroprene involves three different enzymes the carboxylesterases, the cytochrome P450 monooxygenases, and epoxide hydrolase. The latter does not attack until an epoxide has been produced by the P450s. 

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