Induction of metallothionein by stress and its molecular mechanisms.

This article describes the effect of restraint stress or social reorganization stress on the induction of metallothionein (MT) in the liver, heart, lung, and spleen. Both MT-I and MT-II mRNA were elevated as much as 30-fold following just 12 h (one cycle) of restraint stress. The amount of MT protein also increased following stress. The MT induction was the highest in the liver, followed by the lung, heart, and spleen. MT-I induction was also observed in the fore, mid, and hind regions of the brain whereas the brain-specific MT-III gene was not activated by stress. The increase in MT mRNA correlated well with the rise in stress-induced serum corticosterone. The induction occurred at the transcriptional level and was mediated essentially by the activation of glucocorticoid receptor. The MT mRNA returned to the control level after nine cycles of stress. Exposure of these habituated mice to a different type of stress (treatment with heavy metals such as cadmium or zinc sulfate) led to further MT induction. Because heavy metals induced MT via activation of the factor MTF-1, distinct molecular mechanisms should be responsible for the activation of MT promoter by different inducers.