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 infant ile 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 pl ays in generation of the renal Fanconi syndrome, also associated with this disorder, led to speculation that SA might also have neurotoxic e ffects. Thus, we have studied the distribution and impact on heme meta bolism 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 (A LAD) was reduced to less than 10% of control activity in all three tis sues after three daily injections; after a 7-day recovery, activity wa s regained at different rates in the three tissues. Total heme content of each tissue showed a steady decline beyond the treatment period, t he most marked reduction being found in kidney. Porphyrin intermediate s, heme oxygenase activity and cytochrome P-450 content evidenced vary ing responses to SA exposure which differed from tissue to tissue. Our results show that brain tissue sequesters SA and that heme biosynthes is 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.