Kinetics of aluminum-induced inhibition of delta-aminolevulinic acid dehydratase in vitro

Anemia, one consequence of aluminum toxicity, may be due to inhibition of enzymes in the heme biosynthetic pathway. In this study, the in vitro effect of aluminum on rat liver and erythrocyte delta-aminolevulinic acid dehydratase (delta-ALA dehydratase), an enzyme that is sensitive to a number of metal ions, was investigated. The presence of 1-10 mu M AlCl3 caused a concentration-dependent inhibition of liver delta-ALA dehydratase activity. The K-i for AlCl3-induced inhibition of delta-ALA dehydratase was 4.1 mu M, and 10 mu M AlCl3 virtually abolished delta-ALA dehydratase activity (99% inhibition). Erythrocyte delta-ALA dehydratase was also inhibited by similar concentrations of AlCl3 and displayed a K-i of 1.1 mu M. AlCl3 (5 mu M) decreased the V-max by 50% but did not change the K-m, suggestive of reversible, noncompetitive inhibition. Sodium citrate (50 mu M) when added with AlCl3 completely restored delta-ALA dehydratase activity to basal levels. Thus, disruption of delta-ALA dehydratase occurred at low micromolar levels of AlCl3 in vitro, which may help to explain abnormalities in the heme pathway in cases of aluminum poisoning.