Drug-induced porphyrin biosynthesis—XIX: Potentiation of the porphyrin-inducing effects of SKF 525-A in the chick embryo liver by 3,5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine, an inhibitor of ferrochelatase

Abstract

Pretreatment of 17-day-old chick embryos with 2-diethylaminocthyl-2,2-diphenylvalerate hydrochloride (SKF 525-A) resulted in enhancement of hepatic δ-aminolevulinic acid (ALA)-synthetase activity and porphyrin accumulation induced by 3.5-diethoxycarbonyl-1,4-dihydro-2,4,6-trimethylpyridine (DDC). The levels of [ 14C]DDC and its metabolites in chick embryo livers were measured at different times after administration of [ 14C]DDC in the presence and absence of SKF 525-A. It is concluded that the magnitude of inhibition of DDC metabolism following SKF 525-A pretreatment is too small to account for the enhanced inducing effects of DDC. DDC was found to inhibit ferrochelatase in chick embryo liver at doses considerably less than those required to induce ALA-synthetase activity. A dose of DDC was selected for administration to the chick embryo large enough to produce 95 per cent inhibition of ferrochelatase without affecting ALA-synthetase activity. When SKF 525-A was then administered, a marked synergistic effect was observed on ALA-synthetase activity and porphyrin accumulation. It is concluded that DDC, by inhibiting ferrochelatase, enhances the ability of SKF 525-A to induce ALA-synthetase activity and porphyrin accumulation.