Human Flavin-Containing Monooxygenase Substrate Specificity and Role in Drug Metabolism

Author: Cashman J.R.

Source: Current Drug Metabolism, Volume 1, Number 2, September 2000 , pp. 181-191(11)

Publisher: Bentham Science Publishers

Abstract:

The human flavin-containing monooxygenase (FMO3) is a prominent enzyme system that converts nucleophilic heteroatom-containing chemicals, drugs and xenobiotics to more polar materials that are more efficiently excreted in the urine. The substrate specificity for FMO 3 is distinct from that of FMO1. Human FMO3 N-oxygenates primary, secondary and tertiary amines whereas human FMO1 is only highly efficient at N-oxygenating tertiary amines. Both human FMO1 and FMO3 S-oxygenate a number of nucleophilic sulfur-containing substrates and in some cases, does so with great stereoselectivity. Human FMO3 is sensitive to steric features of the substrate and aliphatic amines with linkages between the nitrogen atom and a large aromatic group such as a phenothiazine of at least five carbons are N-oxygenated significantly more efficiently than those substrates with two or three carbons. For amines with smaller aromatic substituents such as phenethylamines, often these compounds are efficiently N-oxygenated by human FMO3. Currently, the most promising non-invasive probe of in vivo human FMO3 functional activity is the formation of trimethylamine N-oxide from trimethylamine that comes from dietary choline. (S)-Nicotine N-1 -oxide formation can also be used as a highly stereoselective probe of human FMO3 function for adult humans that smoke cigarettes. Finally, cimetidine S-oxygenation or ranitidine N-oxidation can also be used as a functional probe of human FMO3. With the recent observation of human FMO3 genetic polymorphism and poor metabolism phenotype in certain human populations, variant human FMO3 may contribute to adverse drug reactions or exaggerated clinical response to certain medications. Knowledge of the substrate specificity for human FMO3 may aid in the future design of more efficacious and less toxic drugs.

Keywords: human flavin; monooxygenase; substrate specificity; xenobiotics; hetrocyclic amines; substrates; methyltolylsulfide

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389200003339135

Publication date: 2000-09-01

• Current Drug Metabolism aims to cover all the latest and outstanding developments in drug metabolism and disposition. The journal serves as an international forum for the publication of timely reviews in drug metabolism. Current Drug Metabolism is an essential journal for academic, clinical, government and pharmaceutical scientists who wish to be kept informed and up-to-date with the latest and most important developments. The journal covers the following areas:
  
  In vitro systems including CYP-450; enzyme induction and inhibition; drug-drug interactions and enzyme kinetics; pharmacokinetics, toxicokinetics, species scaling and extrapolations; P-glycoprotein and transport carriers; target organ toxicity and interindividual variability; drug metabolism and disposition studies; extrahepatic metabolism; phase I and phase II metabolism; recent developments for the identification of drug metabolites and adducts.

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• In this Subject: Anatomy & Physiology ,  Pharmacology
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