Plasma homocysteine concentration does not reflect intracellular liver homocysteine in rats

Objective Elevated plasma homocysteine (Hcy) concentrations have been correlated to a higher incidence of a wide range of disorders such as neural tube defects and cardiovascular disease. Whether plasma Hcy concentration (and changes therein) are an accurate reflection of intracellular concentrations (and changes) in organs like the liver is unknown. Methods Wistar rats were fed Hcy-increasing diets (B-vitamin depletion, high-methionine) for 8 weeks. Plasma and liver concentrations of one-carbon metabolism metabolites, and activity of cystathionine ß-synthase and methylenetetrahydrofolate reductase were measured by LC-MS/MS. Results Plasma and liver Hcy and 5-methyltetrahydrofolate concentrations did not correlate (R=0.60, p=0.09;R=0.18, p=0.63, respectively). Liver Hcy correlated with liver S-adenosylmethionine (R=0.72, p=0.03), but not with liver 5-methyltetrahydrofolate and S-adenosylhomocysteine. The B-vitamin depleted diet increased plasma Hcy (p=0.00) but decreased liver Hcy (p=0.00). The high-methionine diet increased plasma Hcy, but did not alter liver Hcy, S-adenosylmethionine or S-adenosylhomocysteine. The high-methionine diet resulted in an increase in cystathionine ß-synthase and methylenetetrahydrofolate reductase activity. The B-vitamin depleted diet had no effect on the activity of these 2 enzymes. Conclusions Plasma one-carbon metabolite concentrations are not a reflection of liver concentrations. Hcy-increasing diets show several unexpected effects of liver one-carbon components, indicating that one-carbon metabolism is more complex than meets the eye when just looking at plasma concentrations.