Oxidases Cytochrome P450 system

The plasma protein binding of tacrolimus is approximately 99%. Tacrolimus is bound mainly to albumin and alpha-1-acid glycoprotein and has a high level of association with erythrocytes. It is extensively metabolized by the mixed-function oxidase system, primarily the cytochrome P450 system (CYP3A). The disposition of tacrolimus from whole blood was biphasic with a terminal elimination half-life of 11.7 hours in liver transplant patients. 

In plants, the (w-hydroxylase system is responsible for synthesis of the o-hydroxy fatty acid components of cutin and suberin. Kolattukudy has studied the reactions in preparations from Vida faba. NADPH and O2 were cofactors and the enzyme showed typical properties of a mixed-function oxidase. However, the involvement of P450 in the plant system is unproven since, although the hydroxylation is inhibited by CO, the inhibition is not reversed by 420-460 nm light (a property typical for cytochrome P450 systems). Where dihydroxy fatty acids are being synthesized for cutin or suberin, the co-hydroxy fatty acid is the substrate for the second hydroxylation. Like tw-oxidation, mid-chain hydroxylation also requires NADPH and O2 and is located in the endoplasmic reticulum. 

The answers are 34-g, 35-a, 36-d. (Katzung, pp 53—56J There are four major components to the mixed-function oxidase system (1) cytochrome P450, (2) NAD PH, or reduced nicotinamide adenine dinucleotide phosphate, (3) NAD PH—cytochrome P450 reductase, and (4) molecular oxygen. The figure that follows shows the catalytic cycle for the reactions dependent upon cytochrome P450. 

Bergh AF, Strobel HW. 1992. Reconstitution ofthe brain mixed function oxidase system purification of NADPH-cytochrome P450 reductase and partial purification of cytochrome P450 from whole rat brain. J Neurochem 59 575-581. 

The protease inhibitors are partiaiiy metaboiized by the cytochrome P450 oxidase system and have a potentiai for serious interactions with a large number of commonly prescribed drug products metabolized by the same pathway. 

Cyclophosphamide, probably one of the most frequently used anti-cancer drugs, is a pro-drug. It can be given orally as well as intravenously. It is converted by the liver microsomal cytochrome P450 mixed-function oxidase system to its active forms... 

In addition to alcohol dehydrogenase, ethanol can be oxidized to acetaldehyde by the microsomal mixed-function oxidase system (cytochrome P450 2 El), as illustrated in Figure 35.1. Although this microsomal ethanol-oxidizing system probably has minor impor-... 

This enzyme system, also known as the mixed function oxidase system, uses NADPH as a cofactor in the metabolism of ethanol (Figure 23-1, right) and consists primarily of cytochrome P450 2E1, 1A2, and 3A4 (see Chapter 4). 

All oxidases need to have a cofactor to which electrons can be transferred. O2 is a direct electron receiver for some reactions while NADPH and flavoprotein complexes known as the cytochrome Ps can be involved in a complex transfer of reducing and oxidizing power. Cytochrome P450 is a well-studied oxidizing system and is illustrated in Figure 9. (The number which is added as a subscript to the P family refers to the wavelength of maximum absorbance for the species.)... 

Cyclophosphamide in its parent form does not have direct cytotoxic effects, and it must be activated to cytotoxic forms by microsomal enzymes (Figure 55-5). The liver microsomal cytochrome P450 mixed-function oxidase system converts cyclophosphamide to 4-hydroxycyclophosphamide, which is in equilibrium with aldophosphamide. These active metabolites are believed to be delivered by the bloodstream to both tumor and normal tissue, where nonenzymatic cleavage of aldophosphamide to the cytotoxic forms—phosphoramide mustard and acrolein—occurs. The liver appears to be protected through the enzymatic formation of the inactive metabolites 4-ketocyclophosphamide and carboxyphosphamide. 

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