Mixed function oxidases isoenzymes

A potentially powerful probe for sorting out the contribution of hydroperoxide-dependent and mixed-function oxidase-dependent polycyclic hydrocarbon oxidation is stereochemistry. Figure 9 summarizes the stereochemical differences in epoxidation of ( )-BP-7,8-dihydrodiol by hydroperoxide-dependent and mixed-function oxidase-dependent pathways (31,55,56). The (-)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (+)-anti-diol epoxide by both pathways whereas the (+)-enantiomer of BP-7,8-dihydrodiol is converted primarily to the (-)-anti-diol epoxide by hydroperoxide-dependent oxidation and to the (+)-syn-diol epoxide by mixed-function oxidases. The stereochemical course of oxidation by cytochrome P-450 isoenzymes was first elucidated for the methycholanthrene-inducible form but we have detected the same stereochemical profile using rat liver microsomes from control, phenobarbital-, or methyl-cholanthrene-induced animals (32). The only difference between the microsomal preparations is the rate of oxidation. 

CYP450 isoenzymes usually reside on the smooth endoplasmic reticulum, and are classic examples of mixed-function oxidases (or oxygenases) these enzymes oxidize and reduce two substrates simultaneously, and atoms from mole-... 

Metabolism in pediatric patients can be quite different from adults. In the very young infant, drug uptake by the liver is decreased due to reduced transport proteins. The biliary excretion of antibiotics with dual routes of elimination suggests that hepatic transport maturation is even slower than glomerular filtration or renal transport maturation. Overall, mixed function oxidases are present at 30-50% of adult activity, while individual enzymes may be less than 5% of adult activity. In particular, isoenzymes of CYP 2C9 and 1A2 have greatly reduced activity in neonates however, there is a rapid increase in 2C9 activity in the first weeks of life. After birth. Phase I and II enzymes have a programmed order of expression, which is different for each isoenzyme. Some isoenzymes increase in days, others over weeks, and stUI others over months. 

Phase I metabolism Phase I reactions (mainly oxidation, reduction, and hydrolysis) act as a preparation of the drug for the phase II reactions, i.e., a chemically reactive group is produced or uncovered on which the phase II reactions can occur, e.g., -OH, -NH2, -SH, -COOH. Most toxic metabolites are produced by phase I reactions. The P-450 isoenzymes (CYP enzymes), known collectively as the mixed function oxidase system, are found in the endoplasmic reticulum of many cells (notably those of liver, kidney, lung, and intestine) and perform many of these different functionalization reactions. The system requires the presence of molecular oxygen and co-factor nicotinamide adenine dinucleotide phosphate (NADPH) as well as cytochrome P450, NADPH-cytochrome P450 reductase, and lipid. 

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