Effect of cadmium administration in hyperhomocysteinemic mice due to cystathionine beta synthase deficiency

Abstract

Homocysteine, a sulfur-containing amino acid formed during the metabolism of methionine, is commonly slightly elevated in the plasma of the general population. Additionally, we previously found that cystathionine beta synthase-deficient mice, a murine model of hyperhomocysteinemia, exhibit altered activities of xenobiotic metabolizing enzymes (XME), which dispose of foreign chemicals, in the liver. Thus, hyperhomocysteinemia may result in susceptibility to xenobiotics like cadmium, a heavy-metal toxicant found in drinking water, atmospheric air, and food. Consequently, we exposed hyperhomocysteinemic mice to cadmium via their drinking water for one month to analyze the combined effects of hyperhomocysteinemia and cadmium exposure in liver. No difference in plasma homocysteine level was found after cadmium administration in control and hyperhomocysteinemic mice, but the glutathione level was significantly lower in exposed hyperhomocysteinemic mice compared to control mice, reflecting oxidative stress. We therefore analyzed the effect of Cd administration on hepatic XMEs known to be dysregulated in hyperhomocysteinemic mice: paraoxonase 1, a phase I XME, and NAD(P)H:quinone oxidoreductase, a phase II XME. Cadmium exposure negatively affected activity of paraoxonase 1, a calcium-dependent enzyme. Thus, we analyzed another calcium-dependent enzyme known to be dysregulated in liver of hyperhomocysteinemic mice, calpain, which was also significantly lower after cadmium administration. A comparison of the calculated affinities of cadmium docking versus calcium redocking suggested that cadmium ions may inhibit enzymatic activities by preventing the binding of calcium ions. Moreover, the increased NAD(P)H:quinone oxidoreductase activity observed after cadmium administration could indicate the presence of protective mechanisms in liver of mice. In conclusion, although cadmium administration had no effect on plasma homocysteine level, its effects on plasma glutathionine level suggest a susceptibility to cadmium in the condition of hyperhomocysteinemia, which could be countered by an increased NAD(P)H:quinone oxidoreductase activity.