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

Fiona A. Wilson, Joost J. G. C. van den Borne, Alexander Graham Calder, Niamh O'Kennedy, Grietje Holtrop, William Rees, Gerald Lobley

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29 Citations (Scopus)


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 [1-13C,methyl-2H3]methionine or [U-13C]methionine plus [1-13C]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 <12% of estimated tissue production. Hyperhomocysteinemia also increased (P < 0.01) the inflow of homocysteine into most tissues, including heart. These findings indicate that a full understanding of hyperhomocysteinemia needs to include metabolism in a variety of organs, rather than an exclusive focus on the liver. Furthermore, the high influx of homocysteine into cardiac tissue may relate to the known association between homocysteinemia and hypertension.

Original languageEnglish
Pages (from-to)E702-713
Number of pages12
JournalAmerican Journal of Physiology: Endocrinology and Metabolism
Issue number4
Early online date13 Jan 2009
Publication statusPublished - Apr 2009


  • stable isotopes
  • isotopomer analysis
  • homocysteine methylation
  • metabolic models
  • amino-acids
  • plasma homocysteine
  • kinetics
  • methylation
  • insulin
  • disease
  • humans
  • deficiency
  • liver
  • methyltransferase


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