Hereditary tyrosinaemia type I: A long‐term study of the relationship between the urinary excretions of succinylacetone and δ‐aminolevulinic acid

Abstract

Patients with hereditary tyrosinaemia type I (HT) excrete large amounts of succinylacetone (SA) in urine. Owing to structural resemblance of SA to delta-aminolevulinic acid (ALA), SA inhibits the second enzyme in the pathway for haeme biosynthesis, porphobilinogen synthase, resulting in increased urinary ALA excretion. We investigated the relationship between urinary SA and ALA excretions of two patients with different forms of HT (late-infantile and juvenile). In both patients the urinary SA and ALA excretions showed a more or less inverse correlation. The patient with the early-infantile form of HT had a relatively greater increase in urinary SA and ALA excretions in comparison to the patient with the juvenile form of HT. A possible explanation for this unexpected inverse correlation between the urinary excretion of SA and ALA might be a lack of intramitochondrial glycine, a substrate for delta-aminolevulinic acid synthesis. It has been reported previously that high concentrations of SA reversibly and competitively inhibit the transport of glycine through membranes.

Lack of Hemodynamic Effects After Extended Heme Synthesis Inhibition by Succinylacetone in Rats

“…Control: n ϭ 5; SA treated: n ϭ 6. tivity by more than 90% in rats (Tschudy et al, 1981) and effectively lower heme content in tissues. In SA-treated rats, we observed marked increases in both urinary SA and ␦-ALA levels, similar to those levels observed in HT patients (Christensen et al, 1981;Sassa and Kappas, 1982;Tuchman et al, 1987;Schierbeek et al, 1993). Treatment with SA also caused markedly decreased heme levels in all tissues studied, without influencing renal function, iron status, or leukocyte counts.…”

Unified gas chromatographic?mass spectrometric method for quantitating tyrosine metabolites in urine and plasma

“…Hereditary tyrosinemia type I (HT1) is an inborn error of metabolism that may cause liver failure, renal insufficiency and peripheral neuropathy [1][2][3][4]. The underlying genetic defect is a mutation in the gene for fumarylacetoacetate hydrolase (FAH), the last enzyme in the catabolic pathway of tyrosine.…”

Estresse oxidativo em porfiria hepática experimental disparada por succinilacetona - um inibidor da ácido 5-aminolevulínico desidratase

“…The fact that the values of the renal c1earance of ALA by treated animais was similar to that of the control group (Table IV) indicates that the increased leveis of plasma ALA did not suffice to alter an effective renal function [41]. Blood accumulation and urinary excretion of ALA at concentrations above the normal leveis have long been reported in symptomatic AIP carriers [41][42][43] and have been associated with neurological manifestations and hepatoma occurrence in AIP patients.…”

“…Estudos desenvolvidos com culturas de células tratadas com 1,0 mM de ALA mostraram que fibroblastos acumulam 1,5 vezes mais ALA que o meio de cultura na primeira meia hora e apenas 20% aos 90 min, enquanto os hepatócitos se enriquecem com apenas 20% de ALA ao longo de 2 horas de incubação (Costa et ai., 1997). No ambiente intracelular, experimentos realizados com mitocôndrias isoladas e 14C-ALA revelaram que a distribuição intra-e extramitocondrial deste metabólito é de 1: 1 (Medeiros et ai., 1994 Gerald, 1970;Schierbeek et aI., 1993;Floderus et aI., 2006) e TH1 (Berger et aI., 1983;Kappas, 1983;Bechara et aI., 2007), e têm sido associados com as manifestações neurológicas e a ocorrência de hepatocarcinomas nestes pacientes. Estes dados parecem ainda sugerir que os efeitos máximos da SA podem ser observados até uma dose limite entre 10 e 40 mg/kg peso corporal.…”