Using MT−/− mice to study metallothionein and oxidative stress

Mice with null mutations for metallothionein genes MT-1 and MT-2 were used to study the role that metallothionein plays in protecting cellular targets in vivo from oxidative stress. Wild-type (MT+/+) and MT-null (MT−/−) mice were treated with either saline or zinc and exposed to two types of oxidative stress: γ-irradiation or 2-nitropropane. There was no alteration in the antioxidant defense system (superoxide dismutase, catalase, or glutathione peroxidase and glutathione levels) to compensate for the lack of the metallothionein in the MT−/− mice. The amount of oxidative damage to liver DNA, lipids, and proteins were similar for the MT−/− and MT+/+ mice even though the levels of metallothionein in the livers of the saline- or zinc-pretreated MT+/+ mice were 5- to 100-fold greater than found in the MT−/− mice. To determine if metallothionein can protect mice from the lethal effects of ionizing radiation, the mean survivals of MT−/− and MT+/+ mice exposed to whole body γ-irradiation were measured and found to be similar. However, the mean survival increased significantly after zinc pretreatment for both the MT−/− and MT+/+ mice. These results demonstrate that tissue levels of metallothionein do not protect mice in vivo against oxidative stress.