Modulation of Cystathionine β-Synthase Level Regulates Total Serum Homocysteine in Mice

Abstract

Elevated total plasma homocysteine is an independent risk factor in the development of vascular disease in humans. Cystathionine β-synthase (CBS) is an enzyme that condenses homocysteine with serine to form cystathionine. In this article, we describe the effects of modulating CBS activity using a transgenic mouse that contains the human CBS cDNA under control of the zinc-inducible metallothionein promoter (Tg-CBS). In the presence of zinc, Tg-CBS mice have a 2- to 4-fold increase in liver and kidney CBS activity compared with nontransgenic littermates. Transgenic mice on standard mouse chow had a 45% decrease in their serum homocysteine (12.1 to 7.2 μmol/L; P <0.0001) when zinc was added to drinking water, although zinc had minimal effect on their nontransgenic siblings (13.2 μmol/L versus 13.0 μmol/L; P =NS). Tg-CBS mice maintained on a high-methionine, low-folate diet also had significantly lower serum homocysteine compared with control animals (179 μmol/L versus 242 μmol/L; P <0.02). CBS overexpression also significantly lowered serum cysteinylglycine (3.6 versus 2.8 μmol/L; P <0.003) levels and reduced the levels of many amino acids in the liver. We also found that expression of Tg-CBS rescued the severe hyperhomocysteinemia and neonatal lethality of Cbs deletion animals. Our results show that elevating CBS activity is an effective method to lower plasma homocysteine levels. In addition, the creation of an inducible mouse system to modulate plasma homocysteine will also be useful in the study of homocysteine-related vascular disease.