Induction of hepatic cytochrome P-450 by natural steroids: Relationship to the induction of δ-aminolevulinate synthase and porphyrin accumulation in the avian embryo

Abstract

Certain steroid hormones and their metabolites are potent inducers of δ-aminolevulinate synthase, the rate-limiting enzyme for heme biosynthesis in the liver. In this study we examined the influences of a number of natural steroids on the induction of liver cytochrome P-450, δ-aminolevulinate synthase, and protoporphyrin in the chick embryo in ovo, and the effects of “priming” with a small dose of 3,5-dicarbethoxy-1,4-dihydrocollidine (DDC), an inhibitor of ferrochelatase. There was a close relationship between the induction of cytochrome P-450 and δ-aminolevulinate synthase by steroids in experiments with, as well as in experiments without, DDC priming. In most instances, 5β steroids were more potent inducers than were the corresponding 5α epimers: 5β steroids more potently induced δ-aminolevulinate synthase and/or porphyrin accumulation for 11 of 15 steroid pairs tested and cytochrome P-450 for 10 of 14 pairs. With DDC priming, steroid induction of δ-aminolevulinate synthase and protoporphyrin was greatly accentuated, while the increase in cytochrome P-450 was partially prevented. This experimental model, is reminiscent of certain human porphyrias in which clinical expression is probably due in part to interactions of endogenous steroids with genetic deficiencies of heme pathway enzymes, and in which there is in the liver enhanced activity of δ-aminolevulinate synthase and accumulation of heme pathway intermediates, while hepatic cytochrome P-450 content is largely maintained. These features suggest that decreases in the regulatory “free” heme pool(s) in the liver can occur and produce pronounced δ-aminolevulinate synthase induction without the development of a marked deficiency of the major liver hemoprotein, cytochrome P-450.