Drug-induced accumulation of uroporphyrin in chicken hepatocyte cultures. Structural requirements for the effect and role of exogenous iron.
The ability of drugs to cause uroporphyria in hepatocytes from 17-day-old chick embryos has been 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 iron in worsening drug-induced uroporphyria was demonstrated in cultures of hepatocytes; iron also caused preferential accumulation of uroporphyrin from added 5-aminolaevulinate 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 two alternative hypotheses for the drug-induced effect in uroporphyrinogen metabolism are considered.
D000081:Acetamides / Q000494:pharmacology; D000083:Acetanilides; D000622:Aminolevulinic Acid / Q000494:pharmacology; D000818:Animals; D001140:Aroclors / Q000494:pharmacology; D002478:Cells, Cultured; D002642:Chick Embryo; D020111:Chlorodiphenyl (54% Chlorine); D003676:Deferoxamine / Q000494:pharmacology; D003997:Dicarbethoxydihydrocollidine / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008797:Metyrapone / Q000494:pharmacology; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives*; D011166:Porphyrins / Q000378:metabolism*; D014578:Uroporphyrins / Q000378:metabolism*
D000081:Acetamides; D000083:Acetanilides; D001140:Aroclors; D005290:Ferric Compounds; D011166:Porphyrins; D014578:Uroporphyrins; D020111:Chlorodiphenyl (54% Chlorine); D003997:Dicarbethoxydihydrocollidine; D000622:Aminolevulinic Acid; D007501:Iron; D003676:Deferoxamine; D009571:Nitrilotriacetic Acid; C044250:N,N-diethylphenylacetamide; C020326:ferric nitrilotriacetate; D008797:Metyrapone