Decreased liver activity of porphyrin–metal chelatase in hepatic porphyria caused by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Studies in rats and mice

Abstract

1. A difference has been found between rats and mice in their sensitivity to the porphyrogenic effect of drugs. Mice are more sensitive than rats to 3,5-diethoxycarbonyl-1,4-dihydrocollidine, but less sensitive than rats to 2-allyl-2-isopropylacetamide. 2. Use has been made of this difference in sensitivity to ascertain the importance of the decrease of liver porphyrin–metal chelatase activity in porphyria caused by 3,5-diethoxycarbonyl-1,4-dihydrocollidine. Mice, which are more sensitive than rats to the stimulation of 5-aminolaevulinate caused by this drug, are also more sensitive with respect to the decrease of chelatase activity. 3. In both species, after treatment with 3,5-diethoxycarbonyl-1,4-dihydrocollidine, the ratio between chelatase activity and 5-aminolaevulinate activity is linear with respect to the reciprocal of the liver porphyrin concentration. This suggests that under these conditions the degree of porphyrin accumulation depends on the balance between rate of porphyrin formation and rate of porphyrin utilization. 4. Compound SKF 525-A (2-diethylaminoethyl 3,3-diphenylpropylacetate) when given before 3,5-diethoxycarbonyl-1,4-dihydrocollidine prevents the appearance of porphyria in the rat and also largely prevents the decrease of chelatase activity. In the mouse it is much less effective in preventing porphyria and it is almost completely inactive in protecting the chelatase from a decrease in activity. 5. Cycloheximide, when given before 3,5-diethoxycarbonyl-1,4-dihydrocollidine also inhibits the induction of 5-aminolaevulinate synthetase and the appearance of porphyria in the rat, but does not prevent the decrease of chelatase activity. These results suggest that two successive stages can be distinguished in the induction process: a first stage leading to inhibition of haem synthesis and a second stage requiring synthesis of protein in the liver and leading to stimulation of 5-aminolaevulinate synthetase.