Low monoamine oxidase B in peripheral organs in smokers

Abstract

One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,L-[ 11 C]deprenyl and deuterium-substituted L-[ 11 C]deprenyl (L-[ 11 C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke. S moking is a major public health problem affecting multiple organ systems and resulting in Ϸ440,000 deaths per year in the United States alone (1). Yet, we still know very little about the molecular mechanisms underlying smoking behavior and toxicity. In addition, even though tobacco smoke contains Ϸ4,000 chemical compounds, pharmacological studies have focused mainly on nicotine (2). We have shown that smokers have reduced levels of brain monoamine oxidase (MAO; EC 1.4.3.4) and that this is not an effect of nicotine (3-5). MAO oxidizes amines and produces hydrogen peroxide as a byproduct. It is present in virtually every organ in the body and occurs in two different subtypes, MAO A and MAO B, which are different gene products. MAO A and B have different substrate and inhibitor specificities (6). MAO A preferentially oxidizes norepinephrine and serotonin and is selectively inhibited by clorgyline (7), whereas MAO B preferentially breaks down benzylamine and phenylethylamine (PEA), and is selectively inhibited by L-deprenyl (8). Both forms oxidize dopamine and tyramine (9). The relative ratios of MAO A and B in different organs are both organ-and species-dependent, making it difficult to use animals as a model for humans (10).Because MAO is one of the phase I oxidative enzymes (11), and its substrates include many physiologically active amines, including some of those released by nicotine, the documentation of reduced brain MAO B levels ...

Functional brain imaging of tobacco use and dependence

“…Additionally, a human post-mortem study of chronic smokers demonstrated a modest reduction in MAO A binding that did not reach statistical significance (Klimek et al, 2001). Peripheral MAO B is also reduced in cigarette smokers (Fowler et al, 2003b).…”

Demonstration of Isoleucine 199 as a Structural Determinant for the Selective Inhibition of Human Monoamine Oxidase B by Specific Reversible Inhibitors

“…In addition, trans,trans-farnesol, a component of tobacco smoke, is a potent, reversible inhibitor specific for MAO B. 2 Another study has established that 1,4-diphenyl-2-butene (K i ϭ 35 M), a contaminant of polystyrene bridges used for MAO B crystallization, and 1,4-diphenyl-1,3-butadiene (K i ϭ 7 M) are potent, competitive MAO B-specific reversible inhibitors (6,7). Because none of these compounds (see Scheme 1 for their respective structures) inhibit MAO A, a more detailed study of the molecular basis for their specificities could provide opportunities to develop MAO B-selective inhibitors with potential neuroprotective properties.…”

Nicotine: Pharmacology, Toxicity and Therapeutic use

“…The interesting question is whether any of these also contributes to the reinforcing properties of tobacco smoke. It has been known for some time that cigarette smoke inhibits monoamine oxidase (MAO), the enzyme that catalyses the metabolism of monoamine neurotransmitters, such as dopamine, thus potentiating their effects in the brain of smokers and thereby contributing significantly to reward and dependence (Fowler et al, 2003). Nicotine is not directly responsible for this effect (Fowler et al, 1999).…”