An Experimental Model for Hepatic Porphyria Based on the Treatment of Rats with Succinylacetone, a Tyrosine Catabolite

Porphyrias are diseases associated with enzymatic deficiencies in the heme biosynthesis leading to accumulation and urinary excretion of 5-aminolevulinic acid (ALA) and porphyrin intermediates. ALA also accumulates in hereditary tyrosinemia type 1 (HT1), due to the inhibition of ALA dehydratase by succinylacetone (SA), a tyrosine metabolite that is overproduced in HT1. Metal-catalyzed ALA oxidation was shown in vitro to yield 4,5-dioxovaleric acid, a cytotoxic and genotoxic α-oxoaldehyde, and reactive oxygen species which could be coupled with protein, DNA and lipid membrane oxidation. In turn, ALA-treated rats underwent extensive brain and liver oxidative damage. These results are in agreement with our hypothesis that ALA may be implicated in the neurological and hepatic manifestations of porphyrias. We here describe an experimental model for hepatic porphyria induced by SA. Rats (n = 32) were divided into 4 groups: control (I) and groups II - IV, treated with 10, 40 and 80 mg/kg SA methyl ester (SAME), respectively. As expected, plasma and liver ALA levels (mM and mg/mg protein, respectively) were significantly higher in groups II (3.30 ± 0.80 and 0.017 ± 0.006), III (3.99 ± 0.45 and 0.018 ± 0.005) and IV (4.39 ± 0.93 and 0.260 ± 0.012) when compared to the control group (0.48 ± 0.04 and 0.002 ± 0.002) (p < 0.001). A significant increase in urinary ALA levels were observed in groups II and III when compared to control and group IV (p < 0.001), as well as in group IV versus control (p < 0.05). ALA dehydratase inhibition by SAME also resulted in decrements of urinary COPRO levels: 52 ± 15%, 56 ± 30%, and 81 ± 23% for groups II, III and IV, respectively. Carbonyl protein levels were 2 fold higher in group IV than in the control. Consistently with the apparent oxidative status induced by SAME treatment, ultrastructural and histological study of liver samples obtained from SAME-treated rats showed electron-dense granules in the cytosol and mitochondria, which suggests iron release from ferritin. Altogether, these data support the viability of this model for hepatic porphyria induced by SA. Support: FAPESP, CNPq, and Milenio Redoxoma.