Inhibition of betaine-homocysteine S-methyltransferase in rats causes hyperhomocysteinemia and reduces liver cystathionine β-synthase activity and methylation capacity

Methylation of homocysteine (Hcy) by betaine-Hcy S-methyltransferase (BHMT) produces methionine, which is required for S-adenosylmethionine (SAM) synthesis. We have recently shown that short-term dietary intake of S-(Delta-carboxybutyl)-DL-Hcy (D,L-CBHcy), a potent and specific inhibitor of BHMT, significantly decreases liver BHMT activity and SAM concentrations but does not have an adverse affect on liver histopathology, plasma markers of liver damage, or DNA methylation in rats. The present study was designed to investigate the hypothesis that BHMT is required to maintain normal liver and plasma amino acid and glutathione profiles, and liver SAM and lipid accumulation. Rats were fed an adequate (4.5 g/kg methionine and 3.7 g/kg cystine), cysteine-devoid (4.5 g/kg methionine and 0 g/kg cystine), or methionine-deficient (1.5 g/kg methionine and 3.7 g/kg cystine) diet either with or without L-CBHcy for 3 or 14 days. All rats fed L-CBHcy had increased total plasma Hcy (2- to 5-fold) and reduced liver BHMT activity (>90%) and SAM concentrations (>40%). S-(Delta-carboxybutyl)-L-Hcy treatment slightly reduced liver glutathione levels in rats fed the adequate or cysteine-devoid diet for 14 days. Rats fed the methionine-deficient diet with L-CBHcy developed Fatty liver. Liver cystathionine beta-synthase activity was reduced in all L-CBHcy-treated animals, and the effect was exacerbated as time on the L-CBHcy diet increased. Our data indicate that BHMT activity is required to maintain adequate levels of liver SAM and low levels of total plasma Hcy and might be critical for liver glutathione and triglyceride homeostasis under some dietary conditions. (C) 2011 Elsevier Inc. All rights reserved.