The role of betaine‐homocysteine S‐methyltransferase (BHMT) in the regulation of plasma total homocysteine (tHcy)

Abstract

Inhibitors and methyl donor substrates for BHMT were used to study the role of this enzyme in regulating tHcy. Fasted mice were given an intraperitoneal injection of S-(delta-carboxybutyl)-DL-homocysteine (CBHcy; 1 mg), a specific and potent inhibitor of BHMT, and their tHcy and hepatic BHMT protein and activity levels were monitored over a 24 h period. Compared to saline-injected control mice, at 2 h post-injection the CBHcy-treated mice had 87% lower hepatic BHMT activity and a 3.7-fold increase (11.1 vs. 3.0 uM) in tHcy; effects that lasted nearly 8 h but returned to normal by 24 h. The level of hepatic BHMT protein remained constant over the 24 h period, independent of treatment. Two h after injecting the sulfoxide derivative of CBHcy (10 mg) into fasted mice there was a modest reduction of hepatic BHMT activity and a 1.9-fold increase in tHcy. When given an injection of Met (3 mg) or Met plus CBHcy (1 mg), post-Met load tHcy levels were 3.2-fold higher (128 vs. 40 uM) at 2 h post-injection in the mice given CBHcy. CBHcy does not inhibit folate-dependent methionine synthase, or pyridoxal phosphate-dependent cystathionine synthase. 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 the post-Met load rise in tHcy. Supported by NIDDK (DK52501) and IL ARS (50–352) to TAG, and grants from the Czech Academy of Sciences (A4055302) and Research Project (Z40550506) to JJ.