Mixed-function oxidation system

Figure 3. Role of adrenodoxin in the mixed-function oxidation system of adrenal...

Another "OH generating reaction is peroxynitrite decomposition to hydroxyl radical and nitrogen dioxide (see sect. 1.12). Also, actions of ionizing radiation and ultrasounds yielding water molecule decomposition are additional sources of "OH. The hydroxyl radical is probably the main reactive species in the so-called metal-catalyzed oxidation systems (or mixed-function oxidation systems) used in experiments where ascorbate and metal ions are employed (though formation of other products such as high-valency iron species ferryl Fe+4 or perferryl Fe+5 forms cannot be excluded) (N2, S50). 

Species differences with regard to various toxic effects based on such chemical lesions and their localization in particular tissues are understandable on basis of species and tissue differences in the capacity of metabolizing pharmaca. The pharmacon under these circumstances acts as a toxogen (compare pharmacogen). It may be emphasized that, although the microsomal mixed-function oxidative system in the liver cells is generally considered to be a de-... 

Takano T, Miyazaki Y, Araki R. 1988. Interaction of 1,1,1-trichloroethane with the mixed-function oxidation system in rat liver microsomes. Xenobiotica 18 1457-1464. 

Zantac gives rise to three known metabolites, namely (a) ranitidine N-oxide (Z ) ranitidine S-oxide and (c) desmethyl ranitidine. It is observed to be only a weak inhibitor of the hepatic cytochrome P-450 mixed function oxidation system. The plasma half-life ranges between 2 to 3 hours and it usually gets excreted together with its metabolites in the urine. 

Kim K, Kim IH, Lee KY et aL The isolation and purification of a specific protector protein which inhibits enzyme inactivation by a thiol/Fe(III)/02 mixed-function oxidation system. J Biol Chem 1988 263 4704-4711. 

Lipid-soluble xenobiotics are commonly biotra ns formed by oxidation in the drug-metabolizing microsomal system (DMMS). For each description below, choose the component of the microsomal mixed-function oxidase system with which it is most closely associated ... 

Both mirex and chlordecone are microsomal enzyme inducers, and as such enhance the metabolism of compounds oxidized or reduced by the mixed function oxygenase system. For... 

Hepatic microsomal and solubilized mixed-function oxidase systems from the little skate, Baja erinacea, a marine elasmobranch. In Ullrich, V., Hildebrandt, A., Roots, I., Eastabrook, R.W. (Eds.) Microsomes and Drug Oxidations (1976). Pergamon Press, Oxford, pp 16O-I69. 

In addition, oral administration of 1- C-2-hexanone to humans or rats results in the appearance of CO in the expired breath (DiVincenzo et al. 1977, 1978), indicating oxidation/cleavage of the alpha carbon. Administration of SKF525A (a mixed function oxidase inhibitor) to rats before oral administration of 2-hexanone resulted in a marked decrease in the excretion of respiratory CO for the first 4 hours after administration, followed by a marked increase at 4-8 and 12-24 hours. This suggests that this oxidative step is mediated by a microsomal mixed function oxidase system (DiVincenzo etal. 1977). 

Putidaredoxin. Cushman et al. (36) isolated a low molecular iron-sulfur protein from camphor-grown Pseudomonas putida. This protein, putidaredoxin, is similar to the plant type ferredoxins with two irons attached to two acid-labile sulfur atoms (37). It has a molecular weight of 12,000 and shows absorption maxima at 327, 425 and 455 nm. Putidaredoxin functions as an electron transfer component of a methylene hydroxylase system involved in camphor hydroxylation by P. putida. This enzyme system consists of putidaredoxin, flavoprotein and cytochrome P.cQ (38). The electron transport from flavoprotein to cytochrome P.cq is Smilar to that of the mammalian mixed-function oxidase, but requires NADH as a primary electron donor as shown in Fig. 4. In this bacterial mixed-function oxidase system, reduced putidaredoxin donates an electron to substrate-bound cytochrome P. g, and the reduced cytochrome P. g binds to molecular oxygen. One oxygen atom is then used for substrate oxidation, and the other one is reduced to water (39, 40). 

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-... 

FIGURE 21-47 Side-chain cleavage in the synthesis of steroid hormones. Cytochrome P-450 acts as electron carrier in this mixed-function oxidase system that oxidizes adjacent carbons. The process also requires the electron-transferring proteins adrenodoxin and adrenodoxin reductase. This system for cleaving side chains is found in mitochondria of the adrenal cortex, where active steroid production occurs. Pregnenolone is the precursor of all other steroid hormones (see Fig. 21-46). 

The hepatic endoplasmic reticulum possesses oxidative enzymes called mixed-function oxidases or monooxygenase with a specific requirement for both molecular oxygen and a reduced concentration of nicotinamide adenine dinucleotide phosphate (NADPH). Essential in the mixed-function oxidase system is P-450 (Figure 1.12). The primary electron donor is NADPH, whereas the electron transfer involved P-450, a flavoprotein. The presence of a heat-stable fraction is necessary for the operation of the system. 

Hasson, E.P., West, C.A. "Properties of the system for the mixed function oxidation of kaurene and kaurene derivatives in microsomes of the immature seed of Mar ah macrocarpus. Cofactor requirements." Plant Physiol., 1976, 58 473- 78. 

Oxidation is by far the most important Phase I metabolic reaction. One of the main enzyme systems involved in the oxidation of xenobiotics appears to be the so called mixed function oxidases or monooxygenases, which are found mainly in the smooth endoplasmic reticulum of the liver but also occur, to a lesser extent, in other tissues. These enzymes tend to be nonspecific, catalysing the metabolism of a wide variety of compounds (Table 9.2). Two common mixed function oxidase systems are the cytochrome P-450 (CYP-450) and the flavin monoxygenase (FMO) systems (Appendix 12). The overall oxidations of these systems take place in a series of oxidative and reductive steps, each step being catalysed by a specific enzyme. Many of these steps require the presence of molecular oxygen and either NADH or NADPH as co-enzymes. 

---