Biotransformation monoamine oxidase

It has been shown that 3 is biotransformed in a reaction catalysed by monoamine oxidase B to species that cause the selective degeneration of nigrostriatal neurons, giving rise to a Parkinsonian syndrome in man and other primates. Studies of this process have shown that the pyridinium salts 4 and 5 are involved, and that 4 undergoes spontaneous disproportionation to 5 and 3 5 is the putative ultimate neurotoxin. More recent studies have shown that 4 undergoes a spontaneous reaction in pH 7.4 buffer to give methylamine and a product identified as 6. 

Boor PJ, Nelson TJ, Moslen MT, et al. 1981. Allylamine cardiovascular toxicity Modulation of the monoamine oxidase system and biotransformation to acrolein. In Proceedings International Conference Industrial Environmental Xenobiotics, 369-375. 

Of the Phase I reactions, oxidative biotransformations are by far the most common. These reactions are carried out by several oxidative enzyme systems, the most predominant of which is the CYP superfamily of enzymes. Additional oxidative enzymes include FMO, xanthine oxidase, aldehyde oxidase, alcohol and aldehyde dehydrogenases monoamine oxidases, and various peroxidases. Determining the enzyme(s) employed to biotransform any particular substrate will depend on the substrates chemical and physical characteristics as well as functional substituents. This chapter does not describe in detail the mechanism of these various enzymes however, it does illustrate the product(s) (i.e., metabolites) produced by each reaction. 

Oxidative biotransformations, which constitutes the major portion of Phase I reactions, can be catalyzed by either cytochrome P450s (CYP450) or nonmicrosomal enzymes such as flavin-containing monooxygenases (FMOs), monoamine oxidase (MAOs), alcohol dehydrogenase, and aldehyde dehydrogenase. As listed in Table 5.1,... 

Monoamine Oxidases (MAO) There are two MAO isoforms, MAO A and MAO B, both of which are flavoen-zymes that oxidize a wide array of neurotransmitter amines. However, they can also biotransform some xenobiotics. Both MAO isoforms consist of approximately 520 amino acid residues and share approximately 70% sequence identity. Their molecular weights are about 58K Daltons. Both isoforms are expressed in most tissues, though not necessarily in equivalent amounts. More MAO is found in liver and placenta, and least in the spleen. Actually MAO-B is... 

Cashman JR. Monoamine oxidase and flavin-containing monooxygenases. In Guengerich FP, editor. Biotransformation, Vol. 3, Comprehensive Toxicology, first ed. Elsevier Science, Oxford 1997. p 69-96. 

Oxidations are the most common biotransformation reactions that occur with most drugs. There are several classes of enzymes that carry out these reactions cytochrome P450s, flavin monooxygenases, monoamine oxidases, xanthine oxidase, aldehyde oxidases, aldehyde dehydrogenases, and peroxidases. Typical reactions and substrate substructures for each of these classes of enzymes will be described. 

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