Methionine restriction leads to hyperhomocysteinemia and alters hepatic H2S production capacity in Fischer-344 rats

Dietary methionine restriction (MR) increases lifespan in several animal models. Despite low dietary intake of sulphur amino acids, rodents on MR develop hyperhomocysteinemia. On the contrary, MR has been reported to increase H2S production in mice. Enzymes involved in homocysteine metabolism also take part in H2S production and hence, in this study, the impact of MR on hyperhomocysteinemia and H2S production capacity were investigated using Fischer-344 rats assigned either a control or a MR diet for 8 weeks. The MR animals showed elevated plasma homocysteine accompanied with a reduction in liver cysteine content and methylation potential. It was further found that MR decreased cystathionine-beta-synthase (CBS) activity in the liver, however, MR increased hepatic cystathionine-gamma-lyase (CGL) activity which is the second enzyme in the transsulfuration pathway and also participates in regulating H2S production. The relative contribution of CGL in H2S production increased concomitantly with the increased CGL activity. Additionally, hepatic mercaptopyruvate-sulphurtransferase (MPST) activity also increased in response to MR. Taken together, our results suggest that reduced CBS activity and S-Adenosylmethionine availability contributes to hyperhomocysteinimia in MR animals. Elevated CGL and MPST activities may provide a compensatory mechanism for maintaining hepatic H2S production capacity in response to the decreased CBS activity.