title: Decreased global methylation in patients with bipolar disorder who respond to lithium.
abstract: Mitochondrial dysfunction, oxidative stress, and alterations in DNA methylation, are all associated with the pathophysiology of bipolar disorder (BD). We therefore studied the relationship between oxidative stress and DNA methylation in patients with BD with an excellent response to lithium treatment, their affected and unaffected relatives and healthy controls. Transformed lymphoblasts were cultured in the presence or absence of lithium chloride (0.75 mM). DNA and proteins were extracted from the cells to determine levels of 8-hydroxy-2-deoxyguanosine (8-OHdG), 5-methylcytosine (5-mc), mitochondrial complex I and glutathione peroxidase (GPx) activities. Methylation was decreased in BD subjects and their relatives compared to controls and remained so after lithium treatment in BD subjects but not in their relatives. 8-OHdG levels and complex I activity did not differ between groups before and after lithium treatment. Finally, relatives of patients showed increased GPx activity before and after lithium treatment, which negatively correlated with 5-mc levels. Changes in global methylation may be specific for BD and lithium may be involved in glutathione regulation. The present study supports the importance of DNA methylation to the pathophysiology of BD and the therapeutic potential of antioxidants in this illness.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Aya A
authors.initials: AA
authors.lastname: Huzayyin
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Andreazza
authors.affiliation: McGill Group for Suicide Studies, Depressive Disorders Program, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Gustavo
authors.initials: G
authors.lastname: Turecki
authors.affiliation: McGill Group for Suicide Studies, Depressive Disorders Program, Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Cruceanu
authors.affiliation: Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
authors.forename: Guy A
authors.initials: GA
authors.lastname: Rouleau
authors.affiliation: Department of Psychiatry, Dalhousie University, Halifax, NS, Canada.
authors.forename: Martin
authors.initials: M
authors.lastname: Alda
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
authors.forename: L Trevor
authors.initials: LT
authors.lastname: Young
mesh_terms: D000328:Adult; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001714:Bipolar Disorder / Q000188:drug therapy / Q000378:metabolism*; D002478:Cells, Cultured; D019175:DNA Methylation / Q000187:drug effects / Q000502:physiology*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008094:Lithium / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology
chemical_list: D014150:Antipsychotic Agents; D008094:Lithium