Defects in Haem Synthesis in Mammalian Tissues in Experimental Lead Poisoning and Experimental Porphyria

Abstract

1. The biochemical effects of experimental lead poisoning and experimental porphyria induced by allyl-isopropylacetamide have been compared in New Zealand White rabbits. 2. In lead poisoning there was an increase in urinary coproporphyrin excretion within 48 hr of the first dose of lead. Urinary δ-aminolaevulic acid excretion increased about 1 week later and urinary porphobilinogen excretion about 3 weeks later. 3. In lead-poisoned rabbits the activity of the enzyme δ-aminolaevulic acid dehydrase was impaired in the brain, liver, kidney and bone marrow. This inhibition was largely due to interference with the sulphydryl groups of the enzyme. 4. No inhibition of the enzyme haem synthetase could be detected in homogenates prepared from lead poisoned tissues but the addition of lead acetate in concentrations similar to those present in the original unhomogenized tissues produced marked inhibition. 5. There was no increase in either the δ-aminolaevulic acid or the porphobilinogen content of the brain in lead poisoning but the δ-aminolaevulic acid content of the liver, kidney and bone marrow, and the porphobiliogen content of the kidney were significantly increased. 6. Inhibition by lead of the enzymes δ-aminolaevulic acid dehydrase and haem synthetase may explain the biochemical abnormalities observed in lead poisoning. 7. In experimental porphyria the main enzyme abnormality found was a large increase in δ-aminolaevulic acid synthetase activity in the liver with increases in δ-aminolaevulic acid dehydrase activity in the liver and kidney.

Comparative toxicity and tissue distribution of lead acetate in weanling and adult rats.

“…The ALA dehydratase activity of brain appears to be especially sensitive to lead. A 42% inhibition of ALA dehydratase activity occurred when the mean brain lead level was 2.3 Rug/g, while a 50% reduction in the activity of the kidney enzyme occurred with a mean tissue lead level of 29.9 ,ug/g (32).…”

Porphyrin-heme biosynthesis in organotypic cultures of mouse dorsal root ganglia. Effects of heme and lead on porphyrin synthesis and peripheral myelin.

“…Studies in non-nervous tissues such as hematopoietic cells and liver (7)(8)(9)(10)(11)(12) have identified toxic effects of lead on specific enzymes of the heme biosynthetic pathway. Recent studies that used organotypic cultures of dorsal root ganglia derived from the chick (13,14) and the mouse (15) have provided clear evidence for the presence of the porphyrin-heme biosynthetic pathway in this peripheral nervous system tissue.…”

“…The fact that chronic lead exposure produces damage to Schwann cells (3)(4)(5), the demonstration that lead impairs the integrity of the heme biosynthetic pathway (7)(8)(9)(10)(11)(12), and the primary localization of the pathway in the supporting elements of dorsal root ganglia (13)(14)(15) have led us to study the possible relationship between lead-induced demyelination and impaired porphyrin-heme biosynthesis in this model system.…”

Blood cell delta-aminolevulinic acid dehydratase activity in humans exposed to methylmercury.

“…EXiperimental administration of lead causes a-'depressi'On of ALA-D in b.rain tissue (12,25). If a similar depression of ALA-D activity in nervous tissue does occur with methylmercury exposure, it might be of importance in the pathogenesis of the nervous tissue damage in methylmercury poisoning.…”