Oxidation non-microsomal

Non-microsomal oxidations may be subdivided into amine oxidation, alcohol and aldehyde oxidation, dehalogenation, purine oxidation, and aromatization. 

The non-microsomal oxidation is catalysed by enzymes that are free in the cellular plasma or by relatively non-specific enzymes present in the mitochondrial fraction of the homogenized tissue of liver cells. Two of these enzymes which are particularly important are monoaminooxidase, catalysing the metabolism of primary amines and controlling the level of biogenic amines, and diaminooxidase, catalysing selectively the oxidation of one out of two amino groups of diamines. Aliphatic alcohols are oxidized by the alcohol dehydrogenase to aldehydes. This reaction is reversible and the same enzyme participates in the reduction of aldehydes and ketones to alcohols [7]. 

Preston BD, Miller JA, Miller EC. 1983. Non-arene oxide aromatic ring hydroxylation of 2,2,5,5 -tetrachlorobiphenyl as the major metabolic pathway catalyzed by phenobarbital-induced rat liver microsomes. J Biol Chem 258 8304-8311. 

Aldehyde oxidase, a non-microsomal enzyme discussed in more detail below, may also be involved in the oxidation of quinoline to give 2-hydroxyquinoline (Fig. 4.14). The heterocyclic phthalazine ring in the drug hydralazine is oxidized by the microsomal enzymes to phthalazinone. The mechanism, which may involve nitrogen oxidation, is possibly involved in the toxicity of this drug (see chap. 7). Again, other enzymes may also be involved (Fig. 4.15). 

Oxidative reactions catalysed by non-microsomal enzymes are less varied than those mediated by cytochrome P450 mono-oxygenases but are important in the metabolism of some drugs (e.g. isoproterenol, methylxanthines, methimazole, ethanol, chloral hydrate), endogenous substances (adrenalin, histamine) and naturally occurring compounds (vitamin A). Theophylline and caffeine (methylxanthines) simultaneously undergo microsomal cytochrome... 

Certain drugs inhibit non-microsomal metabolic pathways. Metronidazole, like disulfiram, inhibits aldehyde dehydrogenase, the enzyme that normally oxidizes acetaldehyde to acetic acid in the metabolic pathway for ethanol. Allopurinol inhibits xanthine oxidase, the enzyme that catalyses the oxidation of hypoxanthine to xanthine and xanthine to uric acid. Because azathioprine and 6-mercaptopurine are metabolized by xanthine oxidase, the dosage of these drugs (synthetic xanthine analogues), when used concomitantly with... 

Oxidation is an extremely common reaction in all living systems. For the organism, it serves as a source of the energy necessary for synthetic processes and this type of reactions is simultaneously employed for removing toxic substances. According to the site of enzymes catalysing relevant reactions, we can consider two types of oxidation — microsomal and non-microsomal. The oxidation occurs particularly in liver cells and only a small proportion occurs in the skin or in other tissue. 

Oxidations via non-microsomal P450 system Alcohol dehydrogenase (ethanol)... 

The second caveat is that, in order to accurately predict hepatic clearance, the correct in vitro system must be chosen. If the candidate drug is primarily oxidatively metabolized, then liver microsomes will be sufficient. However, if the potential for non-microsomal biotransformation exists, then a different in vitro system, such as hepatocyte suspensions, should be used. In the illustration above, it turned out, as far as clearance of Compound X is concerned, man is specifically like a rat, and unlike a dog. 

Foreign compounds may be metabolized by non-microsomal enzyme systems. These reactions include deamination of amines, oxidation of alcohols and aldehydes, reduction of aldehydes and ketones, hydrolysis of some esters and amides and may occur in the mitochondria, or the cell supernatant fraction, or in the circulating plasma. A thorough discussion of these non-microsomal mechanisms has been presented by Parke [20], These reactions are confined to Phase I oxidations, reductions, and hydrolyses (see Fig. 1). 

Much work has demonstrated the presence of complex multienzyme monooxygenase systems within the endoplasmic reticulum of several mammalian species (for Reviews 1, 2, 3). These monooxygenase systems are responsible for the oxidative metabolism of many exogenous and endogenous substances, and the unusual non-specificity of these monooxygenase enzymes allows the metabolism of compounds with diverse chemical structures. Early work demonstrated that the terminal microsomal oxidase involved in xenobio-tic biotransformation was a hemoprotein, which has been subsequently named cytochrome P-450. 

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