Metallothionein gene expression in mouse tissues by D-penicillamine

The effect of D-penicillamine on metallothionein mRNA accumulation was examined in mouse tissues by Northern and dot blot analysis. This drug was given as a single intraperitoneal dose of 250 mg/kg body weight and the metallothionein mRNA content of the tissues was measured 1, 4, 8 and 24 hours later. A detectable increase of mRNA was observed after 1 hour and maximal accumulation was seen after 4 hours in the liver, kidneys, lungs, brain and spleen, whereas in the heart the maximum occurred after 8 hours. In the liver metallothionein mRNA was increased 14.5-fold over the control and in the kidneys it was increased by a factor of 9.2. A significant increase was also seen in the lungs, where it was 10 fold. To determine whether the increase is due to new transcription of the metallothionein gene, animals were pretreated with actinomycin D (1.0 mg/kg body weight) before receiving D-penicillamine. Actinomycin D prevented some of the D-penicillamine-induced increase in metallothionein mRNA, indicating that the drug, to some extent, acts at the transcriptional level. Regulation of metallothionein gene expression may play an important role in the molecular mechanisms involved in the clinical action of D-penicillamine in rheumatoid arthritis.