title: 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
  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
  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
  quinone oxidoreductase activity.
authors.affiliation: Univ. Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Ramambason
authors.affiliation: Univ. Paris Diderot, Sorbonne Paris Cité, INSERM UMRS-973, MTi, F-75205 Paris, France.
authors.forename: Gautier
authors.initials: G
authors.lastname: Moroy
authors.affiliation: Univ. Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Daubigney
authors.affiliation: AP-HP, Hôpital Européen Georges Pompidou, Service de Biochimie, 75015 Paris, France.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Paul
authors.affiliation: Univ. Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative (BFA), UMR 8251 CNRS, F-75205 Paris, France. Electronic address: janel@univ-paris-diderot.fr.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Janel
mesh_terms: D000818:Animals; D043303:Aryldialkylphosphatase / Q000737:chemistry / Q000378:metabolism; D002104:Cadmium / Q000378:metabolism / Q000633:toxicity*; D002154:Calpain / Q000737:chemistry / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000172:deficiency*; D004195:Disease Models, Animal; D005978:Glutathione / Q000097:blood; D020138:Hyperhomocysteinemia; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D062105:Molecular Docking Simulation
chemical_list: D002104:Cadmium; D043303:Aryldialkylphosphatase; C560867:PON1 protein, mouse; D002154:Calpain; D003541:Cystathionine beta-Synthase; D005978:Glutathione
keywords: Cadmium; Docking; Hyperhomocysteinemia; Liver; Mice; Xenobiotic metabolizing enzymes