Copper metabolism in metallothionein-null mice fed a high-zinc diet

Abstract

Humans and animals develop low copper (Cu) status when fed diets containing large amounts of zinc (Zn) for an extended period. Current theory states that Zn-induced metallothionein (MT) in the intestinal mucosa binds Cu and prevents its absorption. We tested this theory by using a mouse model with a disruption in the MT gene that renders it incapable of producing functional MT-I and MT-II (MT-null). If the theory is true, then the MT-null mouse should not develop low Cu status when fed a high Zn diet. For 1 week, groups of 4-week-old MT-null and control mice were fed a diet that contained 35 mg Zn and < 1 mg Cu/kg. Each genotype was then divided into two groups each. One group was fed a diet containing 35 mg Zn and 1.5 mg Cu/kg and the other was fed a diet containing 400 mg Zn and 1.5 mg Cu/kg. After 14 days, plasma was harvested and plasma ceruloplasmin amine oxidase (CPAO) activity, a good indicator of Cu status, was determined. The plasma CPAO activity of control mice fed 400 mg Zn/kg diet was 50% of that in similar mice fed 35 mg Zn/kg. Likewise, plasma CPAO activity in MT-null mice fed 400 mg Zn/kg diet was 40% of that in MT-null mice fed 35 mg Zn/kg. These data suggest that MT induction is not required for the development of low Cu status in mice fed a high Zn diet and that the actual mechanism may involve the modulation or inhibition of a Cu transporter protein by Zn.