title: Human monoamine oxidase is inhibited by tobacco smoke: beta-carboline alkaloids act as potent and reversible inhibitors.
abstract: Monoamine oxidase (MAO) is a mitochondrial outer-membrane flavoenzyme involved in brain and peripheral oxidative catabolism of neurotransmitters and xenobiotic amines, including neurotoxic amines, and a well-known target for antidepressant and neuroprotective drugs. Recently, positron emission tomography imaging has shown that smokers have a much lower activity of peripheral and brain MAO-A (30%) and -B (40%) isozymes compared to non-smokers. This MAO inhibition results from a pharmacological effect of smoke, but little is known about its mechanism. Working with mainstream smoke collected from commercial cigarettes we confirmed that cigarette smoke is a potent inhibitor of human MAO-A and -B isozymes. MAO inhibition was partly reversible, competitive for MAO-A, and a mixed-type inhibition for MAO-B. Two beta-carboline alkaloids, norharman (beta-carboline) and harman (1-methyl-beta-carboline), were identified by GC-MS, quantified, and isolated from the mainstream smoke by solid phase extraction and HPLC. Kinetics analysis revealed that beta-carbolines from cigarette smoke were competitive, reversible, and potent inhibitors of MAO enzymes. Norharman was an inhibitor of MAO-A (K(i)=1.2+/-0.18 microM) and MAO-B (K(i)=1.12+/-0.19 microM), and harman of MAO-A (K(i)=55.54+/-5.3nM). Beta-carboline alkaloids are psychopharmacologically active compounds that may occur endogenously in human tissues, including the brain. These results suggest that beta-carboline alkaloids from cigarette smoke acting as potent reversible inhibitors of MAO enzymes may contribute to the MAO-reduced activity produced by tobacco smoke in smokers. The presence of MAO inhibitors in smoke like beta-carbolines and others may help us to understand some of the purported neuropharmacological effects associated with smoking.
authors.affiliation: Spanish Council for Scientific Research, CSIC, Instituto de Fermentaciones Industriales, Juan de la Cierva, 3, 28006, Madrid, Spain. therraiz@ifi.csic.es <therraiz@ifi.csic.es>
authors.forename: Tomas
authors.initials: T
authors.lastname: Herraiz
authors.forename: Carolina
authors.initials: C
authors.lastname: Chaparro
mesh_terms: D000470:Alkaloids / Q000032:analysis / Q000097:blood / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007700:Kinetics; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D010084:Oxidation-Reduction; D013050:Spectrometry, Fluorescence; D014028:Tobacco Smoke Pollution / Q000009:adverse effects* / Q000032:analysis
chemical_list: D000470:Alkaloids; D008996:Monoamine Oxidase Inhibitors; D014028:Tobacco Smoke Pollution; D008995:Monoamine Oxidase