A MUTANT MOUSE (TX) WITH INCREASED HEPATIC METALLOTHIONEIN STABILITY AND ACCUMULATION

Metallothioneins (MTs) are low-molecular-mass cysteine-rich proteins i mplicated in metal homoeostasis and resistance to toxicity induced by heavy metals and alkylating agents. We report high hepatic MT protein accumulation (greater than 100-fold compared with wild-type mice) in t oxic milk (tx) mice, along with markedly higher cytosol copper and zin c levels. Increased MT-gene transcription alone could not account for the high constitutive MT protein levels, since MT mRNA levels were not increased in tx mouse livers. However, hepatic MT was significantly m ore stable in adult tx mice: MT half-life (t1/2) was 79 or 77% greater than in wild-type mice before and after Cd induction respectively. Cd or Zn treatment increased MT mRNA, but not MT protein, accumulation i n tx mouse livers: Cd displaced MT-bound Zn and Cu in preexisting MT. Thus tx mice appear to accumulate hepatic MT as a result of decreased protein degradation. These animals may provide a useful model to study the physiological role of MT, and human diseases (such as Wilson's di sease) with abnormal copper metabolism.