- DNA methylation is coupled with one-carbon metabolism involving homocysteine/methionine interconversion. Correlation between plasma homocysteine levels and leukocyte global DNA methylation was reported but not always replicated. Nicotinamide N-methyltransferase (NNMT) is a determinant of plasma homocysteine levels. Findings suggest alteration of one-carbon metabolism in schizophrenia etiology; hyperhomocysteinemia was observed in schizophrenia. A recent study carried out by the authors of this paper found an association between NNMT and schizophrenia and decreased postmortem brain NNMT mRNA levels. The present study assessed the interrelationship between brain and leukocytes global DNA methylation and plasma homocysteine levels, and between hyperhomocysteinemia and brain NNMT expression. Mice were administered homocysteine in drinking water. Percentage global genome DNA methylation was measured using the cytosine-extension method, and NNMT expression was measured using real-time quantitative reverse transcriptase PCR (qRT-PCR). Homocysteine administration resulted in a 10-fold increase in plasma homocysteine. However, there was no change in global DNA methylation in lymphocytes or in the frontal cortex. No significant intra-individual correlation was found between global DNA methylation in leukocytes and frontal cortex, suggesting that leukocyte global DNA methylation may not serve as a marker for brain global DNA methylation. No difference was found in NNMT expression in homocysteine-treated mice compared with control mice. In conclusion, relatively short-term hyperhomocysteinemia in mice does not reproduce or lead to alterations reported in one-carbon metabolism in disorders associated with lifelong elevated plasma homocysteine.