Effect of drugs on heme synthesis in the liver

Abstract

Several substances have been shown to affect hepatic heme synthesis in the rat liver. Phenobarbital and the polycyclic hydrocarbon, 3,4-benzpyrene, produce an induction of aminolevulinic acid synthetase (ALAS), the enzyme mediating the first step in heme synthesis. This is followed sequentially by increased incorporation of glycine into microsomal heme, increased microsomal protoheme, cytochrome P-450, and increases in activity of certain microsomal mixed function oxidate reactions. Microsomal cytochrome b5 is not altered during such events. 3-amino-1,2,4-triazole inhibits increases in hepatic heme synthesis and drug oxidations produced by phenobarbital and 3,4-benzyprene, but has no effect on ALAS changes or cytochrome b5. Ferrchelatase, an enzyme mediating the last step in heme synthesis, is also increased by phenobarbital treatment. This enzyme was shown to be inhibited by lead and prior administration to the animal of 3,5-diethoxycarbonyl-2,4,6-trimethylpyridine (DDC). DDC also induces ALAS activity. The combined increase in ALAS activity and inhibition of ferrochelatase by DDC could account for the profound porphyria produced by this agent.