The effect of metalloporphyrins and heme liposomes on δ-aminolevulinate synthase activity in rat liver

Abstract

Heme administration causes inhibition of δ-aminolevulinate synthase (ALAS), best tested in the allylisopropylacetamide (AIA)-treated rat, a model for hepatic porphyrias. Because heme suspended in aqueous media (for injection) is unstable and has adverse effects on coagulation, alternate therapeutic modalities are being explored. The present study tries to answer two questions: 1) are any heme analogs as effective inhibitors of ALAS as heme is; and 2) does heme administration in the form of liposomes increase its effectiveness? None of the liposome compositions tested, even if containing lactosylceramide for preferential hepatocyte uptake, was more effective in inhibiting AIA-induced ALAS activity than heme in buffer. As for the function of the heme analogs, although deuteroheme and heme dimethyl ester proved ineffective, mesoheme and cobalt protoporphyrin were nearly as effective as heme itself, indicating that both hydrophobic side chains in positions 2 and 4 and free propionate groups at 6 and 7 are essential for ALAS inhibition, as is the presence of a central cobalt or iron atom.