Smoking induces long-lasting effects through a monoamine-oxidase epigenetic regulation.
BACKGROUND
Postulating 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.


RESULTS
5-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
This 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.
Launay
Jean-Marie
JM
Service de Biochimie et Biologie Moléculaire/Equipe Associée (EA) 3621, Assistance Publique des Hôpitaux de Paris, Hôpital Lariboisière, Faculté de Pharmacie, Université Paris Descartes, Paris, France.
Del Pino
Muriel
M
Chironi
Gilles
G
Callebert
Jacques
J
Peoc'h
Katell
K
Mégnien
Jean-Louis
JL
Mallet
Jacques
J
Simon
Alain
A
Rendu
Francine
F
D000328:Adult; D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D006801:Humans; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D051379:Mice; D008875:Middle Aged; D008995:Monoamine Oxidase / Q000235:genetics* / Q000502:physiology; D010974:Platelet Aggregation; D012306:Risk; D012701:Serotonin / Q000378:metabolism; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics
D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D008995:Monoamine Oxidase