Methionine-induced hyperhomocysteinemia promotes superoxide anion generation and NFkappaB activation in peritoneal macrophages of C57BL/6 mice.

It is well documented that hyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis. This study was designed to investigate whether some of the atherosclerotic effects ascribed to HHcy are mediated by oxidative stress and nuclear factor kappa B (NFkappaB) activation in peritoneal macrophages of C57BL/6 mice fed a high (2%) methionine/low (1 mg/kg) folate diet for 12 weeks. Plasma homocysteine concentrations in mice fed methionine averaged 49 mol/L after 12 weeks of feeding, five times higher than that of controls. HHcy induced by methionine feeding significantly elevated oxidative stress, as measured by superoxide anion radical level (P <.05) in peritoneal macrophages. Furthermore, NFkappaB binding activities of peritoneal macrophages were higher in the methionine group than in the control group. These results suggest that HHcy induced by methionine may intensify disturbances in peroxidation and inflammatory mediator activation in peritoneal macrophages, and is a possible mechanism of its atherogenic effects.