EFFECTS OF MIFEPRISTONE (RU-486) ON HEME METABOLISM AND CYTOCHROMES P-450 IN CULTURED CHICK-EMBRYO LIVER-CELLS - POSSIBLE IMPLICATIONS FOR ACUTE PORPHYRIA

Mifepristone (RU-486), a potent progesterone receptor antagonist and i nducer of cytochromes P-450, is currently in use in Europe, particular ly as a post-coital oral contraceptive. Soon it will be available in t he United States, as well. Since progesterone has been implicated in t he pathogenesis of acute attacks of porphyria, the use of RU-486 or re lated compounds might be considered in porphyric patients. However, as with other cytochrome P-450 inducers, RU-486 may have the ability to precipitate or exacerbate attacks of acute porphyria. The acute porphy rias in relapse are associated with an increase in activity of delta-a minolevulinic acid synthase, the first and normally rate-controlling e nzyme in heme biosynthesis. We have used primary cultures of chick emb ryo liver cells to test the ability of RU-486 to induce delta-aminolev ulinic acid synthase activity and mRNA, cytochromes P-450, porphyrin a ccumulation, and heme oxygenase. We found that RU-486, at concentratio ns observed in human plasma after a single oral dose, induced the mRNA and activity of delta-aminolevulinic acid synthase, both by itself an d in the presence of deferoxamine, a potent iron chelator that inhibit s ferrochelatase. RU-486 and deferoxamine together also produced signi ficant accumulations of protoporphyrin. These results indicate that RU -486 may pose a risk in patients with known acute porphyria and should be used with caution. RU-486 increased the concentration of total cyt ochrome P-450, and the activity of erythromycin demethylase, an activi ty specifically catalyzed by cytochrome P-450 3A. Unlike several other porphyrogens (e.g. hydantoins, barbiturates), RU-486 does not produce accumulation of uroporphyrin or induction of heme oxygenase in chick embryo liver cells.