Monoamine oxidases MAOs EC 1434

Monoamine oxidases (MAOs) are described elsewhere in this book (see 5.05 Principles of Drug Metabolism 1: Redox Reactions). The major function of MAOs consists of the inactivation by oxidative deamination of monoamine

Table 2 Substrate specificity of pig liver flavin-containing monooxygenase (FMO)

Organic nitrogen compounds

Secondary and tertiary cyclic and acyclic amines N-Alkyl- and N,N-dialkyl arylamines Hydrazines Organic sulfur-containing compounds

Mercaptopurines, -pyrimidines, and -imidazoles Cyclic and acyclic sulfides and disulfides Thioamides, thiocarbamides, dithiocarbamides, dithioacids Other organic substrates Boronic acid Phosphines Selenides Selenocarbamides Inorganic compounds

Sulfur, sulfides, thiocyanates Iodine, iodides, hypoiodites

Reproduced from Oesch, F.; Arand, M. Xenobiotic Metabolism. In Toxicology, Marquardt, H., Schafer, S. G., McClellan, R., Welsch, F., Eds.; Academic Press: New York, 1999, pp 83-109, with permission from Elsevier.

neurotransmitters such as serotonin and dopamine. MAO also metabolizes many xenobiotic primary, secondary, or tertiary amines thereby generating an amine (or ammonia), an aldehyde, and hydrogen peroxide:

The hydrogen peroxide formed can reach toxicologically relevant levels.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an interesting example of metabolism-related selective toxicity. It is toxified via the intermediate 1-methyl-4-phenyl-2,3-dihydropyridinium salt (MPDP +) to the 1-methyl-4-phenyl pyridinium salt (MPP+). MPP+ is taken up by a high-affinity reuptake system specifically localized in the nigrostriatal dopaminergic neurons and blocks their mitochondrial energy metabolism. This leads to death of these neurons, which causes Parkinson's disease. Within the neurons only MAO can metabolize MPTP, while in other tissues CYP- and FMO-catalyzed detoxification reactions compete with MAO for the substrate. This combination of selective uptake into cells possessing a selective pattern of drug-metabolizing enzymes causes the selective neurotoxicity. MPTP is an experimental chemical. Related compounds such as beta-carboline or tetrahydroisoquinoline are present at low concentrations in food. Whether they behave in a similar way to MPTP and therefore are neurotoxicologically important by contributing to the etiology of idiopathic Parkinson's disease is unclear.1

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