Steroid induction of delta-aminolevulinic acid synthase and porphyrins in liver. Structure-activity studies and the permissive effects of hormones on the induction process.
Quantitative aspects and structure-activity relationships of the inducing effects of natural steroids on delta-aminolevulinic acid (ALA) synthase and porphyrins have been investigated in monolayer cultures of chick embryo liver cells maintained in a serum-free medium as well as in the chick embryo liver in ovo. Many 5 alpha and 5 beta metabolites of neutral C-19 and C-21 hormones and hormone precursors stimulated porphyrin formation and ALA-synthase induction in the cultured liver cells as we have previously described. In these inducing actions a number of 5 beta epimers (A:B cis) were found to be more potent than their corresponding 5 alpha epimers (A:B trans). The structure-activity relationship between 5 beta and 5 alpha steroid epimers with respect to ALA-synthase induction in culture was also found to prevail with respect to induction of this enzyme in chick embryo liver in ovo. Hemin in concentrations of 2 x 10(-7) M inhibited steroid induction of porphyrin formation, and CaMgEDTA enhanced the responsiveness of the cultured liver cells to steroids by approximately 10 times. The addition of insulin, or insulin plus hydrocortisone or insulin plus hydrocortisone plus triiodothyronine, was important for the maintenance of protein synthesis and essential for maximal expression of the ability of steroids to induce porphyrins and ALA-synthase in the "permissive" effect which insulin, hydrocortisone, and triiodothyronine exert on allylisopropylacetamide induction of porphyrins and ALA-synthase also extends to the induction process which is elicited by natural steroids. These findings also strongly suggest that the regulation of hepatic porphyrin-heme biosynthesis by endogenous as well as exogenous chemicals is significantly influenced by the internal hormonal milieu.
D000624:5-Aminolevulinate Synthetase / Q000096:biosynthesis*; D000731:Androstanes / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002642:Chick Embryo; D004492:Edetic Acid / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005043:Etiocholanolone / Q000494:pharmacology; D006427:Hemin / Q000494:pharmacology; D006854:Hydrocortisone / Q000494:pharmacology; D007328:Insulin / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008274:Magnesium / Q000494:pharmacology; D011166:Porphyrins / Q000096:biosynthesis*; D011278:Pregnanes / Q000494:pharmacology; D013256:Steroids / Q000494:pharmacology*; D014284:Triiodothyronine / Q000494:pharmacology
D000731:Androstanes; D007328:Insulin; D011166:Porphyrins; D011278:Pregnanes; D013256:Steroids; D014284:Triiodothyronine; D006427:Hemin; D005043:Etiocholanolone; D004492:Edetic Acid; D000624:5-Aminolevulinate Synthetase; D008274:Magnesium; D002118:Calcium; D006854:Hydrocortisone