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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Inhibition of Betaine-Homocysteine S-Methyltransferase Causes Hyperhomocysteinemia in Mice^1,2

Michaela Collinsova^*,3, Jana Strakova^*, Jiri Jiracek and Timothy A. Garrow^*,4

^* Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801 and Biological Chemistry Department, Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic,16610 Prague 6, Czech Republic

⁴ To whom correspondence should be addressed. Email: tagarrow{at}uiuc.edu.

Inhibitors and methyl donor substrates for betaine-homocysteine S-methyltransferase (BHMT) were used to study the role of this enzyme in the regulation of plasma total homocysteine (tHcy). Mice were administered an i.p. injection of S-(-carboxybutyl)-DL-homocysteine (CBHcy; 1 mg), a specific and potent inhibitor of BHMT, and tHcy and hepatic BHMT protein and activity levels were monitored over a 24-h period. Compared with saline-injected control mice, at 2 h postinjection, the CBHcy-treated mice had 87% lower BHMT activity and a 2.7-fold increase (11.1 vs. 3.0 µmol/L) in tHcy, effects that lasted nearly 8 h but returned to normal by 24 h. The level of BHMT protein remained constant over the 24-h period. After 6 CBHcy (1 mg) injections (one every 12 h), the mice had 7-fold higher tHcy, a 65% reduction in the liver S-adenosylmethionine:S-adenosylhomocysteine ratio, and a marked upregulation of BHMT protein expression. At 2 h after injection of the sulfoxide derivative of CBHcy (10 mg) into mice, there was a modest reduction in BHMT activity and a 90% increase in tHcy. When given an injection of Met (3 mg) or Met plus CBHcy (1 mg), post-Met load tHcy levels were 2.2-fold higher (128 vs. 40 µmol/L) at 2 h postinjection in the mice given CBHcy. Like betaine, dimethylsulfoniopropionate was an effective tHcy-lowering agent when given with a Met load. These studies are the first to show that transient inhibition of BHMT in vivo causes transient hyperhomocysteinemia, and that dimethylsulfoniopropionate can reduce a post-Met load rise in tHcy.

KEY WORDS: • betaine • homocysteine • dimethylsulfoniopropionate

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