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Title: | Role of Betaine-Homocysteine S-Methyltransferase in Homocysteine Methylation |
Author(s): | Strakova, Jana |
Doctoral Committee Chair(s): | Nakamura, Manabu T. |
Department / Program: | Food Science and Human Nutrition |
Discipline: | Food Science and Human Nutrition |
Degree Granting Institution: | University of Illinois at Urbana-Champaign |
Degree: | Ph.D. |
Genre: | Dissertation |
Subject(s): | Chemistry, Biochemistry |
Abstract: | In mouse liver homogenates, 1000 mumol/L D,L-CBHcy did not inhibit methionine synthase, CBS and cystathionase activities but 5 mumol/L D,L-CBHcy completely inhibited BHMT activity indicating, that D,L-CBHcy was a specific inhibitor of BHMT. To address whether BHMT inhibition caused hyperhomocysteinemia, mice were injected with 1mg of D,L-CBHcy. This reduced BHMT activity (87%) and elevated total plasma Hcy (tHcy, 2.7-fold) for 8 hours. Repeated intraperitoneal injections of D,L-CBHcy (6 doses) additionally reduced the liver S-adenosylmethionine-to-S-adenosylhomocysteine ratio (65%). To assess whether BHMT inhibition affected liver and plasma amino acids, rats were fed 5mg D,L-CBHcy (9 doses). Plasma methionine and serine decreased (23 and 17%, respectively), while histidine, Hcy and glycine increased (35, 311 and 24% respectively). There were no changes in liver methionine and Hcy, but liver taurine, serine, and glutamate decreased (74, 50 and 46%, respectively). Increased plasma betaine (1465%) confirmed that BHMT was functionally inhibited in vivo. Interestingly, liver CBS activity and protein levels decreased (56 and 26%, respectively). To assess whether BHMT inhibition affected glutathione levels and/or caused fatty liver, rats were fed either an adequate (4.5g/kg methionine, 3.7g/kg cystine); cystine-devoid (4.5g/kg methionine, 0g/kg cystine) or a methionine-deficient diet (1.5g/kg methionine, 3.7g/kg cystine) alone or in combination with L-CBHcy for 3, 7 or 14 days. L-CBHcy treatment reduced liver glutathione in rats fed the adequate and cysteine-devoid diets. All animals fed the methionine-deficient diet with L-CBHcy developed fatty liver. L-CBHcy treatment decreased liver CBS activity (15--74%) and the effect was exacerbated with time. We conclude that BHMT activity is required for normal levels of plasma Hcy and methionine, liver SAM and glutathione, and CBS activity. |
Issue Date: | 2008 |
Type: | Text |
Language: | English |
Description: | 107 p. Thesis (Ph.D.)--University of Illinois at Urbana-Champaign, 2008. |
URI: | http://hdl.handle.net/2142/83711 |
Other Identifier(s): | (MiAaPQ)AAI3314907 |
Date Available in IDEALS: | 2015-09-25 |
Date Deposited: | 2008 |
This item appears in the following Collection(s)
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Dissertations and Theses - Food Science and Human Nutrition
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Graduate Dissertations and Theses at Illinois
Graduate Theses and Dissertations at Illinois