Dietary intake of S-(alpha-carboxybutyl)-DL-homocysteine induces hyperhomocysteinemia in rats.

Abstract

Betaine homocysteine S-methyltransferase (BHMT) catalyzes the transfer of a methyl group from betaine to homocysteine (Hcy), forming dimethylglycine and methionine. We previously showed that inhibiting BHMT in mice by intraperitoneal injection of S-(alpha-carboxybutyl)-DL-homocysteine (CBHcy) results in hyperhomocysteinemia. In the present study, CBHcy was fed to rats to determine whether it could be absorbed and cause hyperhomocysteinemia as observed in the intraperitoneal administration of the compound in mice. We hypothesized that dietary administered CBHcy will be absorbed and will result in the inhibition of BHMT and cause hyperhomocysteinemia. Rats were meal-fed every 8 hours an L-amino acid-defined diet either containing or devoid of CBHcy (5 mg per meal) for 3 days. The treatment decreased liver BHMT activity by 90% and had no effect on methionine synthase, methylenetetrahydrofolate reductase, phosphatidylethanolamine N-methyltransferase, and CTP:phosphocholine cytidylyltransferase activities. In contrast, cystathionine beta-synthase activity and immunodetectable protein decreased (56% and 26%, respectively) and glycine N-methyltransferase activity increased (52%) in CBHcy-treated rats. Liver S-adenosylmethionine levels decreased by 25% in CBHcy-treated rats, and S-adenosylhomocysteine levels did not change. Furthermore, plasma choline decreased (22%) and plasma betaine increased (15-fold) in CBHcy-treated rats. The treatment had no effect on global DNA and CpG island methylation, liver histology, and plasma markers of liver damage. We conclude that CBHcy-mediated BHMT inhibition causes an elevation in total plasma Hcy that is not normalized by the folate-dependent conversion of Hcy to methionine. Furthermore, metabolic changes caused by BHMT inhibition affect cystathionine beta-synthase and glycine N-methyltransferase activities, which further deteriorate plasma Hcy levels.

• Authors: Jana Strakova, Kelly T Williams, Sapna Gupta, Kevin L Schalinske, Warren D Kruger, Rima Rozen, Jiri Jiracek, Lucas Li, Timothy A Garrow
• Journal: Nutrition research (New York, N.Y.) (Nutr Res) Vol. 30 Issue 7 Pg. 492-500 (Jul 2010) ISSN: 1879-0739 [Electronic] United States
• PMID: 20797482 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Inc. All rights reserved.

Chemical References

• Amino Acids
• Enzyme Inhibitors
• Homocysteine
• Betaine
• S-Adenosylmethionine
• 5-(delta-carboxybutyl)homocysteine
• S-Adenosylhomocysteine
• Glycine N-Methyltransferase
• Betaine-Homocysteine S-Methyltransferase
• Cystathionine beta-Synthase
• Choline

Topics

• Amino Acids (analysis, blood)
• Animals
• Betaine (blood)
• Betaine-Homocysteine S-Methyltransferase (antagonists & inhibitors)
• Choline (blood)
• Cystathionine beta-Synthase (analysis, metabolism)
• Diet
• Enzyme Inhibitors (administration & dosage)
• Glycine N-Methyltransferase (metabolism)
• Homocysteine (administration & dosage, analogs & derivatives, pharmacokinetics)
• Hyperhomocysteinemia (chemically induced, pathology)
• Liver (chemistry, enzymology, pathology)
• Male
• Rats
• Rats, Inbred F344
• S-Adenosylhomocysteine (analysis)
• S-Adenosylmethionine (analysis)