Studies on the role of heme in the regulation of delta-aminolevulinic acid synthetase during fetal hepatic development.

The role of heme in the regulation of δ-aminolevulinic acid (ALA) synthetase was studied in fetal rat liver. The activity of ALA synthetase, the first and rate-limiting enzyme in the heme-biosynthetic pathway, is 10 times higher in fetal rat liver mitochondria than in adults. Hemin injection depresses mitochondrial ALA synthetase activity in the adult but not in the fetus. Cycloheximide, a selective inhibitor of protein synthesis in cytoplasmic ribosomes, but not in mitochondria, causes a rapid decrease in fetal mitochondrial ALA synthetase activity. When hemin is given prior to cycloheximide, a slower rate of turnover of mitochondrial ALA synthetase activity occurs than after cycloheximide alone. Treatment with 3-amino-1,2,4-triazole, an inhibitor of δ-aminolevulinic acid dehydratase, the second enzyme in heme biosynthesis, causes a decrease in fetal mitochondrial ALA synthetase activity but no decrease in the extramitochondrial enzyme levels. These studies indicate that heme may facilitate the development of mitochondrial ALA synthetase in fetal rat liver. It is suggested that ALA synthetase may not become rate-limiting in hepatic heme biosynthesis until it becomes susceptible to repression by heme, a phenomenon which does not develop until near the time of birth.