The inhibitory effect of coproporphyrins on amino acid uptake into proteins by porphyric liver cells

Abstract

Steroids, drugs and certain chemicals stimulate the synthesis of porphyrins in avian liver cells by inducing the de novo formation of 6-aminolevulinate synthetase (ALAS), the rate-limiting enzyme in the porphyrinheme biosynthetic pathway [l-3]. This chemicallyinduced hepatic porphyria has proved to be a useful experimental model for examining pathogenetic mechanisms in the natural disorders of porphyrin metabolism in man. The excess porphyrins synthesized by avian liver cells treated with porphyrinogenic chemicals accumulate in these cells in very high concentrations [ 1,4] ; similarly high concentrations of porphyrins accumulate in the liver in certain of the human porphyrias. The pharmacological effects which these porphyrins may have on the various metabolic processes of hepatic cells are not known. In the course of other studies, we observed that in liver cells treated with the potent porphyrinogenic agent allylisopropylacetamide (AIA), the incorporation of “C-leucine into proteins in vitro was significantly less than in untreated cultures. This effect was unexpected in light of the known increase in liver enzyme synthesis which takes place in experimental porphyria [5,6] ; moreover the inhibition of 14C-leucine incorporation into protein was observed only during the latter part of the induction period when porphyrins are present in great excess in the treated hepatic cells. Such inhibition was also noted when exogenous b-aminolevulinic acid (ALA) was added to the cultures and transformed by the cell into porphyrins. These findings led us to examine the direct effects of porphyrins on amino acid incorporation into protein by cultured liver cells. The results of these experi-