Smoking Induces Long-Lasting Effects through a Monoamine-Oxidase Epigenetic Regulation

Abstract

BackgroundPostulating that serotonin (5-HT), released from smoking-activated platelets could be involved in smoking-induced vascular modifications, we studied its catabolism in a series of 115 men distributed as current smokers (S), never smokers (NS) and former smokers (FS) who had stopped smoking for a mean of 13 years.Methodology/Principal Findings5-HT, monoamine oxidase (MAO-B) activities and amounts were measured in platelets, and 5-hydroxyindolacetic acid (5-HIAA)—the 5-HT/MAO catabolite—in plasma samples. Both platelet 5-HT and plasma 5-HIAA levels were correlated with the 10-year cardiovascular Framingham relative risk (P<0.01), but these correlations became non-significant after adjustment for smoking status, underlining that the determining risk factor among those taken into account in the Framingham risk calculation was smoking. Surprisingly, the platelet 5-HT content was similar in S and NS but lower in FS with a parallel higher plasma level of 5-HIAA in FS. This was unforeseen since MAO-B activity was inhibited during smoking (P<0.00001). It was, however, consistent with a higher enzyme protein concentration found in S and FS than in NS (P<0.001). It thus appears that MAO inhibition during smoking was compensated by a higher synthesis. To investigate the persistent increase in MAO-B protein concentration, a study of the methylation of its gene promoter was undertaken in a small supplementary cohort of similar subjects. We found that the methylation frequency of the MAOB gene promoter was markedly lower (P<0.0001) for S and FS vs. NS due to cigarette smoke-induced increase of nucleic acid demethylase activity.Conclusions/SignificanceThis is one of the first reports that smoking induces an epigenetic modification. A better understanding of the epigenome may help to further elucidate the physiopathology and the development of new therapeutic approaches to tobacco addiction. The results could have a larger impact than cardiovascular damage, considering that MAO-dependent 5-HT catabolism is also involved in addiction, predisposition to cancer, behaviour and mental health.

Molecular aspects of monoamine oxidase B

“…1. MAO B expression is up-regulated by decreased methylation, as observed in smokers (Launay et al, 2009). This was tested and confirmed in HeLa cells incubated with a DNA methyltransferase inhibitor resulting in decreased methylation of the MAO B promoter and increased MAO B expression (Wong et al, 2003).…”

The Emerging Theoretical Framework of Life Course Health Development

“…This research includes studies regarding epigenetic programming associated with fetal exposure to chemical compounds, environmental toxicants, and smoking (Skinner et al 2008;Launay et al 2009;Perera et al 2009;Martino and Prescott 2011), as well as studies examining the impact of nutritional stresses on metabolic function and future disease (Li et al 2010).…”

Smoking, but Not Malnutrition, Influences Promoter-Specific DNA Methylation of the Proopiomelanocortin Gene in Patients with and without Anorexia Nervosa

“…15,17,64 Additional animal experiments support a causal relation between smoking and reduced DNA methylation. 15 If indeed smoking has an influence on POMC methylation and subsequent α-MSH and adrenocorticotropic hormone secretion, this could help to explain why smokers as a group have a lower body weight and why weight increases after cessation of smoking are common. 65,66 However, it could also be speculated that altered POMC promoter methylation represents a vulnerability toward nicotine dependence through altered HPA activity.…”