RESUMO
The administration of diacetylmorphine (DAM) reduces the activation of the hypothalamic-pituitary-adrenal (HPA) axis in opioid-maintained patients. However, the epigenetic effects of DAM on addiction-related genes have not been investigated yet. In a randomized controlled study, we examined the immediate effects of intravenous DAM versus placebo on the promoter methylation of the POMC (pro- opiomelanocortin) and NR3C1 (glucocorticoid receptor 1) genes. Twenty-eight heroin-dependent patients on DAM-assisted treatment received either DAM or saline in a randomized crossover design and 17 healthy participants received saline only. EDTA blood samples were taken 25 min before and 10 min after the injection of DAM or saline. We found reciprocal regulation effects for DAM versus saline application regarding the methylation of POMC; while DAM injection significantly increased methylation, saline injection led to a significant decrease in methylation for patients as well as controls. NR3C1 data did not show significant changes in methylation. Injection of DAM blunted stress hormone levels and the POMC promoter methylation of heroin-dependent patients. These findings provide first preliminary insights into the epigenetic mechanisms underlying the emotional regulation effects of DAM-assisted treatment in severe heroin-dependent patients.
Assuntos
Metilação de DNA/efeitos dos fármacos , Dependência de Heroína/tratamento farmacológico , Heroína/administração & dosagem , Entorpecentes/administração & dosagem , Pró-Opiomelanocortina/genética , Receptores de Glucocorticoides/genética , Administração Intravenosa , Adulto , Estudos Cross-Over , Emoções/efeitos dos fármacos , Emoções/fisiologia , Epigênese Genética/efeitos dos fármacos , Feminino , Dependência de Heroína/genética , Dependência de Heroína/metabolismo , Dependência de Heroína/psicologia , Humanos , Masculino , Pró-Opiomelanocortina/metabolismo , Regiões Promotoras Genéticas , Receptores de Glucocorticoides/metabolismo , Fatores de Tempo , Resultado do TratamentoRESUMO
The level of epigenetic DNA methylation is an important factor in the pathogenesis of various human diseases. As smoking may influence DNA methylation, we investigated the effect of smoking habits on global DNA methylation in 298 genomic DNA samples (73 fathers, 69 mothers and 156 offspring). We did not find a direct effect of smoking on global DNA methylation. However, there was an association of the offspring's DNA methylation with paternal DNA methylation that was strongest if both had never smoked (R2corr=0.41, Beta=0.68, p=0.02) and completely vanished if the offspring smoked or had ever smoked. These findings suggest an association between smoking behaviour and global DNA methylation, which may be of importance for a wide range of diseases.