Tissue methionine cycle activity and homocysteine metabolism in female rats: impact of dietary methionine and folate plus choline

1 The Rowett Institute of Nutrition and Health (RINH), University of Aberdeen, Bucksburn, Aberdeen, United Kingdom; 2 Animal Nutrition Group, Department of Animal Sciences, Wageningen University, Wageningen, The Netherlands; and 3 Provexis plc and 4 Biomathematics and Statistics Scotland, RINH, University of Aberdeen, Aberdeen, United Kingdom Submitted 6 August 2008 ; accepted in final form 9 January 2009 Impaired transfer of methyl groups via the methionine cycle leads to plasma hyperhomocysteinemia. The tissue sources of plasma homocysteine in vivo have not been quantified nor whether hyperhomocysteinemia is due to increased entry or decreased removal. These issues were addressed in female rats offered diets with either adequate or excess methionine (additional methyl groups) with or without folate and choline (impaired methyl group transfer) for 5 wk. Whole body and tissue metabolism was measured based on isotopomer analysis following infusion with either [1- 13 C,methyl- 2 H 3 ]methionine or [U- 13 C]methionine plus [1- 13 C]homocysteine. Although the fraction of intracellular methionine derived from methylation of homocysteine was highest in liver (0.18–0.21), most was retained. In contrast, the pancreas exported to plasma more of methionine synthesized de novo. The pancreas also exported homocysteine to plasma, and this matched the contribution from liver. Synthesis of methionine from homocysteine was reduced in most tissues with excess methionine supply and was also lowered in liver ( P < 0.01) with diets devoid of folate and choline. Plasma homocysteine concentration ( P < 0.001) and flux ( P = 0.001) increased with folate plus choline deficiency, although the latter still represented