In vivo stable isotope measurements of methyl metabolism: Applications in pathophysiology and interventions

Abstract

With intravenous infusion of doubly-labeled [2H3C-1-13C-] methionine and stable isotope enrichments in plasma free methionine and carbon dioxide in breath air, whole body transmethylation, transsulfuration, and remethylation rates can be calculated. This technique demonstrated impaired recycling as the major disturbance to explain hyperhomocysteinemia in patients with end-stage renal failure, and can be used to optimize interventions with folate, B6 and B12 supplementation in this patient group. Intravenous infusion of [2,3,3-2H3] serine has also been applied to demonstrate the appearance of [2H2]- as well as [2H1]- methionine in plasma and protein, suggesting transfer of a one-carbon group from serine via 5,10-methylenetetrahydrofolate in human hepatocyte cytosol and mitochondria, respectively. In sheep, tissue free methionine enrichments after infusion of universally labeled [U-13C] methionine showed the highest remethylation activity in postmortem investigation of jejunum, liver, and kidney tissue samples, but no such activity in muscle and brain samples. Methods to quantitate one-carbon acceptor metabolism pathways and folate metabolism have recently become available.