Abstract:

Porphyrinogen and heme synthesis in whole blood, hemolysates, and supernatant of hemolysates from lead-poisoned rabbits and control rabbits were studied in vitro. [2-14C]Glycine, δ-aminolaevulic acid, δ-amino[4-14C]laevulic acid, porphobilinogen, [14C]uroporphyrinogen III, [14C]coproporphyrinogen III and Fe2+ ions were the basic substrates employed. With [2-14C]glycine as the subtrate, free porphyrinogen synthesis by teh lead-poisoned system was depressed as was depressed as was incorporation of the substrate into heme. When starting with δ-aminolaevulic acid, there was a general decrease in all porphyrinogens synthesized, but most particularly for uro- and phyriaporphyrinogens. Incorporation of δ-amino[4-14C]laevulic acid into heme was also diminished. In contrast, when porphobilinogen and [24C]uroporphyrinogen III were the substrates, there were no significant differences in porphyrin synthesis between the lead-poisoned and control systems and comparable amounts of uroporphyrinogen III and phyriaporphyrinogen III were metabolized. Nevertheless, an accumulation of phyriaporphyrinogen III, relative to the amounts of coproprophyrinogen III, occured. These results demonstrate that one of the principal blocks in the biosynthetic pathway of protorporphyrin in lead poisoning is at the δ-aminolaevulic acid dehydrase (EC 4.2.1.24) level, and that a second block, quantitatively less important, occurs between phyriaporphyrinogen III and coproporhyrinogen III. [14C]Coproporphyrinogen III inorporation into protopohyrin 9 and heme was decreased in the lead-poisoned systems. The well-documented accumulation of both these intermediates could be satisfactorily explained on the basis of lead impairing the transport of iron or other metabolites through the mitochondrial membrane. © 1965.