Abstract

3-Amino-1,2,4-triazole inhibits rat hepatic δ-aminolevulinic acid dehydratase (EC 4.2.1.24), the enzyme which mediates the second step in heme biosynthesis. Aminotriazole decreases the incorporation of both δ-aminolevulinic acid-¹⁴C and ⁵⁹Fe into microsomal heme and inhibits the stimulation of ⁵⁹Fe incorporation into microsomal heme produced by phenobarbital. Aminotriazole also inhibits the induction of rat hepatic microsomal cytochrome P-450 and that of the microsomal oxidations of ethylmorphine, norcodeine, and 3-methyl-4-monomethylaminoazobenzene produced by phenobarbital during the first 48 hr of treatment.

Since aminotriazole has no effect on the induction of the hepatic microsomal flavoprotein NADPH-cytochrome c reductase by phenobarbital, it appears to inhibit the biosynthesis of heme exclusive of an effect on protein synthesis. It is suggested that heme synthesis may be the controlling event in the synthesis of the microsomal hemoprotein cytochrome P-450, and that stimulation of heme synthesis represents one means by which phenobarbital produces an increase of cytochrome P-450 in hepatic microsomes.