Role of haem in the induction of cytochrome P-450 by phenobarbitone. Studies in chick embryos in ovo and in cultured chick embryo hepatocytes

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Abstract
The role of heme synthesis during induction of hepatic cytochrome P-450 hemoproteins was studied in chick embryos in ovo and in chick embryo hepatocytes cultured under chemically defined conditions. Phenobarbitone promptly increased 5-aminolevulinate synthase activity, the rate-limiting enzyme of heme biosynthesis, and the concentration of cytochrome P-450. This induction response occurred without measurable initial destruction of the heme moiety of cytochrome P-450. When intracellular heme availability was enhanced by exogenous heme or 5-aminolevulinate, phenobarbitone-mediated induction of cytochrome P-450 was not affected in spite of the well known repression of 5-aminolevulinate synthase by heme. These data are consistent with the concept that heme does not regulate the synthesis of cytochrome P-450 hemoproteins. Acetate inhibited heme biosynthesis at the level of 5-aminolevulinate formation. When intracellular heme availability was diminished by treatment with acetate, phenobarbitone-mediated induction was decreased. This inhibitory effect of acetate on cytochrome P-450 induction was reversed by exogenous heme or its precursor 5-aminolevulinate. Inhibition of heme biosynthesis probably did not decrease synthesis of apo-cytochrome P-450. Exogenous heme can be incorporated into newly formed apo-cytochrome P-450.

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