"Glucose effect" and rate limiting function of uroporphyrinogen synthase on porphyrin metabolism in hepatocyte culture: relationship with human acute hepatic porphyrias

Abstract

The effect of glucose on drug-promoted induction of porphyrin synthesis was studied in chick embryo liver cell culture with and without the addition of exogenous delta-aminolaevulinic acid (ALA). Induction of ALA synthase was abolished by haemin or glucose. Less than 10% of porphobilinogen is converted into protoporphyrin. Protoporphyrin synthesis cannot be enhanced by high ALA concentrations. The conversion of exogenous ALA into porphyrins decreases with increasing concentrations of ALA from 0.1 to 2.0 mmol/l, whereas porphobilinogen accumulates, thus reflecting the rate limiting function of uroporphyrinogen synthase, which is not influenced by glucose. This needle-eye-like function of uroporphyrinogen synthase within the porphyrin biosynthetic chain explains the urinary increase of ALA and porphobilinogen in the acute phase of variegate and coproporphyria, similar to that in acute intermittent porphyria. The "glucose effect" was also investigated in vivo in humans in 32 courses of hereditary acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria, coproporphyria and porphobilinogen synthase defect porphyria). Patients were treated with high carbohydrate intake (approximately 500 g/24 h), mainly in the form of glucose infusions. There was a resulting consistent and highly significant decrease of porphyrin biosynthesis metabolites, accompanied by clinical improvement in most of the patients.