Inhibition of betaine-homocysteine S-methyltransferase causes hyperhomocysteinemia in mice.
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-(delta-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 micromol/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 micromol/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.
Collinsova
Michaela
M
Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
Strakova
Jana
J
Jiracek
Jiri
J
Garrow
Timothy A
TA
D000818:Animals; D050940:Betaine-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020138:Hyperhomocysteinemia / Q000209:etiology*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D051779:Sterol Regulatory Element Binding Proteins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D051779:Sterol Regulatory Element Binding Proteins; D050940:Betaine-Homocysteine S-Methyltransferase