Microsomal oxidations deamination

Ni et al. [143] investigated the profile of the major metabolites of primaquine produced by in vitro liver microsomal metabolism, with silica gel thin-layer and high performance liquid chromatography analysis. Results indicated that the liver microsomal metabolism could simultaneously produce both 5-hydroxyprimaquine (quinoline ring oxidation product) and carboxyprimaquine (side-chain oxidative deamination product). However, the quantitative comparative study of microsomal metabolism showed that the production of 5-hydroxyprimaquine was far much higher than that of carboxyprimaquine. 

MAO is a flavoprotein enzyme that is found on the outer membrane of mitochondria. It oxidatively deaminates short-chain monoamines only, and it is not part of the DMMS. ATP is involved in the transfer of reducing equivalents through the mitochondrial respiratory chain, not the microsomal system. 

Microsomal oxidations may be subdivided into aromatic hydroxylation aliphatic hydroxylation alicyclic hydroxylation heterocyclic hydroxylation N-, S-, and O-dealkylation N-oxidation N-hydroxylation S-oxidation desulfuration deamination and dehalogenation. 

Studies with various subcellular fractions are useful to ascertain which enzyme systems are involved in the metabolism of a chug candidate. In the absence of added cofactors, oxidative reactions such as oxidative deamination that are supported by mitochondria or by Ever microsomes contaminated with mitochondria membranes (as is the case with microsomes prepared from frozen liver samples) are likely catalyzed by monoamine oxidase (MAO), whereas oxidative reactions supported by cytosol are likely catalyzed by aldehyde oxidase and/or xanthine oxidase (a possible role for these enzymes in the metabolism of... 

Ketones resulting from metabolic oxidative deamination processes are also susceptible to reduction. For instance, rabbit liver microsomal preparations metabolize amphetamine to phenylacetone, which is reduced subsequently to I-... 

Monoamine oxidases are integral outer mitochondrial membrane proteins that catalyze the oxidative deamination of primary and secondary amines as well as some tertiary amines. MAO occurs as two enzymes, MAO-A and MAO-B, which differ in substrate selectivity and inhibitor sensitivity (Abell and Kwan, 2001 Edmondson et al., 2004 Shih et al., 1999). A number of MAO inhibitors have been developed for clinical use as antidepressants and as neuroprotective drugs. Clinically used drug substances include, among others, moclobemide, a relatively selective reversible MAO-A inhibitor, and L-deprenyl, an irreversible selective inhibitor of MAO-B. In vitro, clorgyline and L-deprenyl are used as selective irreversible inhibitors of MAO-A and B, respectively. (Note For in vitro studies using irreversible inhibitors, preincubation of the irreversible inhibitor with the enzyme prior to initiation of the substrate reaction is required for optimal inhibition.) Expressed MAO-A and MAO-B are not readily available via commercial resources however, MAO-A and MAO-B have been evaluated and are active in subcellular fractions. While monoamine oxidases are located in the mitochondria, many microsomal preparations are contaminated with monoamine oxidases during the preparation of the microsomal subcellular fraction and thus microsomes are sometimes used to evaluate monoamine oxidase activity in combination with selective inhibitors. 

A number of phenylisopropylamines which are resistant to degradation by monoamine oxidase are oxidatively deaminated by microsomal enzymes. Among the substrates for this reaction are amphetamine, methamphetamine, ephedrine, and norephedrine the products are a ketone and ammonia ... 

As well as the microsomal enzymes involved in the oxidation of amines, there are a number of other amine oxidase enzymes which have a different subcellular distribution. The most important are the monoamine oxidases and the diamine oxidases. The monoamine oxidases are located in the mitochondria within the cell and are found in the liver and also other organs such as the heart and central nervous system and in vascular tissue. They are a group of flavoprotein enzymes with overlapping substrate specificities. Although primarily of importance in the metabolism of endogenous compounds such as 5-hydroxytryptamine they may be involved in the metabolism of foreign compounds. The enzyme found in the liver will deaminate secondary and tertiary aliphatic amines as well as primary amines, although the latter are the preferred substrates... 

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). 

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