Drug-induced accumulation of uroporphyrin in chicken hepatocyte cultures. Structural requirements for the effect and role of exogenous iron

Abstract

The ability of drugs to cause uroporphyria in hepatocytes from 17-day-old chick embryos was investigated and the response of the cells in culture compared with that of the intact liver of the embryos in ovo. In this chick-embryo system, drugs that cause accumulation of uroporphyrin within 19-24 h can only do so in culture; in contrast, 2-allyl-2-isopropylacetamide and 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which stimulate production of protoporphyrin, are effective both in culture and in ovo. A role of exogenous Fe in worsening drug-induced uroporphyria was demonstrated in cultures of hepatocytes; iron also caused preferential accumulation of uroporphyrin from added 5-aminolevulinate in the absence of a porphyrogenic chemical. Uroporphyria was induced in cultures of hepatocytes by drugs of widely different structures, suggesting that the primary molecular target with which they interact may be relatively aspecific in its binding characteristics. These results are briefly discussed, and 2 alternative hypotheses for the drug-induced effect in uroporphyrinogen metabolism are considered.