Tissue distribution of succinylacetone in the rat in vivo: a possible basis for neurotoxicity in hereditary infantile tyrosinemia.

Neurologic dysfunction is a significant component of hereditary infantile tyrosinemia, an autosomal recessive disorder of man. The specific enzyme defect leads to endogenous production of the biochemical marker compound, succinylacetone (SA). Earlier study of the role which SA plays in generation of the renal Fanconi syndrome, also associated with this disorder, led to speculation that SA might also have neurotoxic effects. Thus, we have studied the distribution and impact on heme metabolism of SA in brain, liver and kidney from rats treated in vivo. Our results show far greater retention of SA in brain and kidney than in liver, by a ratio of approx. 3:1. Delta-aminolevulinate dehydratase (ALAD) was reduced to less than 10% of control activity in all three tissues after three daily injections; after a 7-day recovery, activity was regained at different rates in the three tissues. Total heme content of each tissue showed a steady decline beyond the treatment period, the most marked reduction being found in kidney. Porphyrin intermediates, heme oxygenase activity and cytochrome P-450 content evidenced varying responses to SA exposure which differed from tissue to tissue. Our results show that brain tissue sequesters SA and that heme biosynthesis in brain, as distinct from liver and kidney, is adversely affected. Such effects could result in impaired oxidative metabolism in brain, producing the CNS manifestations of tyrosinemia.