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Hepatic conversion of porphobilinogen to porphyrins was less than 50% of control levels in human subjects with the genetic disease, intermittent acute porphyria. This relative block in heme biosynthesis may be relevant to a concomitant 6- to 10-fold elevation in delta-aminolevulinic acid synthetase activity, since this first and rate-controlling enzyme in the biosynthetic pathway is subject to negative feedback regulation by the end product, heme. A micro-radio-chemical assay of delta-aminolevulinic acid synthetase, and some of its applications, are described.

The excessive induction of hepatic delta-aminolevulinic acid synthetase in rats after the administration of porphyria-inducing compounds is prevented by prior treatment with phenobarbital. Studies in vivo and in vitro indicate that phenobarbital prevents the induction of chemical porphyria by increasing the rate of detoxification of inducers by way of drug-metabolizing enzymes of the hepatic endoplasmic reticulum.

Reciprocal control mechanisms between hemoprotein and 8-aminolevulinic acid synthetase take part in coordinate synthesis of the heme and apoenzyme moieties of tryptophan pyrrolase. Stimulation of heme biosynthesis increases tryptophan pyrrolase, whereas enhancement of heme binding by apotryptophan pyrrolase secondarily increases the formation of delta-aminolevulinic acid synthetase, the rate-limiting enzyme in heme formation. Tryptophan-mediated induction of delta-aminolevulinic acid synthetase suggests that heme participates in repression of that enzyme

The present study confirms the existence of hepatic delta-aminolevulinic acid synthetase in the cytosol of the liver, suggests that this enzyme may be in transit to the mitochondria, and defines some of the characteristics of the partially purified enzyme. The substrate and cofactor requirements are similar to those of mitochondrial delta-aminolevulinic acid synthetase. Heme strongly inhibits the partially purified enzyme. A number of proteins that bind heme block this inhibition, which explains previous failures to demonstrate heme inhibition in crude systems. End-product inhibition of delta-aminolevulinic acid synthetase in the mitochondria may play an important role in the regulation of heme biosynthesis in eukaryotic cells.