Amine oxidases and monooxygenases in the in vivo metabolism of xenobiotic amines in humans: has the involvement of amine oxidases been neglected?

Abstract

In this review, the major enzyme systems involved in vivo in the oxidative metabolism of xenobiotic amines in humans are discussed, i.e. the monooxygenases [cytochrome P450 system (CYPs) and flavin-containing monooxygenases (FMOs)] and the amine oxidases (AOs). Concerning the metabolism of xenobiotic amines (drugs in particular) by monoamine oxidases (MAOs), this aspect has been largely neglected in the past. An exception is the extensive investigation carried out on the inhibition of the metabolism of tyramine, when tyramine-containing food is ingested by subjects taking inhibitors of MAO A or of both MAO A and B. Moreover, investigations in humans on the metabolism of drug amines on the market by AOs, such as semicarbazide-sensitive amine oxidases (SSAOs) and polyamine oxidases (PAOs), are practically nonexistent, with the exception of amlodipine. In contrast to MAOs, monooxygenases (CYP isoenzymes more than FMOs) have been extensively investigated concerning their involvement in the metabolism of xenobiotics. It is possible that the contribution of AOs to the overall metabolism of xenobiotic amines in humans is underestimated or erroneously estimated, as most investigations of drug metabolism are performed using in vitro test systems optimized for CYP activity, such as liver microsomes, and most investigations of drug metabolism in vivo in humans carry out only the identification of the final, stable metabolites. However, for some drugs on the market, the involvement of MAOs in their in vivo metabolism in humans has been demonstrated recently, among these drugs citalopram, sertraline and the triptans are examples that can be mentioned.

Recent adaptive selection at MAOB and ancestral susceptibility to schizophrenia

“…Taking into account recent work suggesting the widespread nature of adaptive selection in recent evolutionary history, associated to the colonization of novel environments during the expansion of humans out of Africa, MAOB seems to remain as a valid candidate of a recently selected locus [Hawks et al, 2007]. Furthermore, MAOB catalyses the oxidative deamination of both biogenic monoamines, mainly dopamine, as well as xenobiotic amines, present in a large variety of foods and beverages [Strolin Benedetti et al, 2007]. Thus, it is involved in traits exposed to major environmental changes, such as cultural behavior or dietary adaptation.…”

Alzheimer’s disease as a systems network disorder: chronic stress/dyshomeostasis, innate immunity, and genetics

“…However, these are generic detoxification enzymes that are abundantly expressed in many tissues outside the CNS, where they act on diverse amine and catechol compounds of endogenous and exogenous origins. The role of monoamine oxidases and COMT in metabolism of endogenous and xenobiotic compounds outside the CNS may have been underappreciated [ 221 ].…”

Recent advances in the prediction of non‐CYP450‐mediated drug metabolism

“…For example, almotriptan is metabolized by ALDH, and MAO‐A by different oxidative pathways (oxidation and deamination) . Very few computational studies and methods directly probe the substrate potential of any given compounds for these enzymes . Thus, predictive models for these enzyme systems are often limited to inhibitor prediction and there is a need for development of regioselective and isoform‐specific substrate prediction models for these systems.…”