Effects of mifepristone (RU‐486) on heme metabolism and cytochromes P ‐450 in cultured chick embryo liver cells

Abstract

Mifepristone (RU-486), a potent progesterone receptor antagonist and inducer of cytochromes P-450, is currently in use in Europe, particularly as a post-coital oral contraceptive. Soon it will be available in the United States, as well. Since progesterone has been implicated in the pathogenesis of acute attacks of porphyria, the use of RU-486 or related 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 porphyrias in relapse are associated with an increase in activity of 8-aminolevulinic acid synthase, the first and normally rate-controlling enzyme in heme biosynthesis. We have used primary cultures of chick embryo liver cells to test the ability of RU-486 to induce b-aminolevulinic acid synthase activity and mRNA, cytochromes P-450, porphyrin accumulation, and heme oxygenase. We found that RU-486, at concentrations observed in human plasma after a single oral dose, induced the mRNA and activity of b-aminolevulinic acid synthase, both by itself and in the presence of deferoxamine, a potent iron chelator that inhibits ferrochelatase. RU-486 and deferoxamine together also produced significant 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 cytochrome P-450, and the activity of erythromycin demethylase, an activity 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.The porphyrias are metabolic diseases characterized by a partial block in heme biosynthesis which causes an accumulation of porphyrins and porphyrin precursors. In the acute porphyrias, the accumulation of heme biosynthetic intermediates is associated with an uncontrolled induction of hepatic S-aminolevulinic acid (ALA) synthase, the first and normally rate-limiting enzyme in heme biosynthesis (for reviews see [l -41). Although almost all of the enzymes in the heme biosynthetic pathway have been implicated as the primary defect in various types of porphyria, the induction of ALA synthase is a feature common to all clinical cases with signs or symptoms of acute porphyria [l-41. In contrast, the chronic por-

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“…A similar impairment by MPA of endothelial function in the brachial artery of young women has been reported [46]. In support of this presumed inverse relationship between progesterone receptors and HO-1 activity, Cable et al [47] demonstrated that the treatment of cultured chick embryo liver cells with mifepristone, a selective progesterone receptor blocker, increases HO activity. Further, reciprocal changes in HO-1 expression (increases) and serum progesterone (decreases) have been shown to associate the antitumor activity of melatonin in the rat mammary carcinoma model [48] and the high glucose induced steroidogenesis in adrenal cells [49].…”

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“…Hemin and butyric acid, known stimulators of all enzymes in the heme synthesis pathway (144,146,149), were shown to stimulate PpIX accumulation in leukemic cells treated with zero or low concentrations of ALA (103,150). The progesterone receptor antagonist mifepristone was found to induce accumulation of PpIX when combined with DFO (in the absence of ALA) in primary chicken liver cells (151).…”

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“…The clinician also screens for other contraindications, including chronic adrenal failure or longterm corticosteroid therapy (because of mifepristone's antiglucocorticoid effect), hemorrhagic disorders or concurrent anticoagulant use, presence of an intrauterine device, inherited porphyria (given the possible increased risk of precipitating an attack), and allergy to mifepristone, misoprostol, or other prostaglandins. 27,28 Pretreatment laboratory testing commonly includes hemoglobin to assess for anemia and blood type to determine Rhesus (Rh) status. 18 Vaginal bleeding after medication administration (discussed in detail below) is unlikely to be well tolerated by women with severe anemia.…”