title: Tissue methionine cycle activity and homocysteine metabolism in female rats: impact of dietary methionine and folate plus choline.
abstract: 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)H3]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 <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.
authors.affiliation: Obesity and Metabolic Health Division, The Rowett Institute of Nutrition and Health, University of Aberdeen, Greenburn Road, Bucksburn, Aberdeen AB21 9SB, UK.
authors.forename: Fiona A
authors.initials: FA
authors.lastname: Wilson
authors.forename: Joost J G C
authors.initials: JJ
authors.lastname: van den Borne
authors.forename: A Graham
authors.initials: AG
authors.lastname: Calder
authors.forename: Niamh
authors.initials: N
authors.lastname: O'Kennedy
authors.forename: Grietje
authors.initials: G
authors.lastname: Holtrop
authors.forename: William D
authors.initials: WD
authors.lastname: Rees
authors.forename: Gerald E
authors.initials: GE
authors.lastname: Lobley
mesh_terms: D000818:Animals; D001823:Body Composition / Q000187:drug effects; D002794:Choline / Q000008:administration & dosage / Q000494:pharmacology*; D004032:Diet; D004044:Dietary Proteins / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D006710:Homocysteine / Q000378:metabolism*; D008715:Methionine / Q000378:metabolism* / Q000493:pharmacokinetics; D008954:Models, Biological; D051381:Rats; D014018:Tissue Distribution
chemical_list: D004044:Dietary Proteins; D006710:Homocysteine; D005492:Folic Acid; D008715:Methionine; D002794:Choline