Sassa S, Kappas A
J Clin Invest. 1983 Mar;71(3):625-34. doi: 10.1172/jci110809.
Succinylacetone (4,6-dioxoheptanoic acid) is an abnormal metabolite produced in patients with hereditary tyrosinemia as a consequence of an inherited deficiency of fumarylacetoacetate hydrolase. It is known that patients with this hereditary disease excrete excessive amounts of delta-aminolevulinic acid (ALA) in urine and that certain patients have an accompanying clinical syndrome resembling that of acute intermittent porphyria (AIP). In order to elucidate the relation of succinylacetone to the heme biosynthetic pathway, we have examined the effects of this metabolite on the cellular heme content of cultured avian hepatocytes and on the activity of purified ALA dehydratase from normal human erythrocytes and from mouse and bovine liver. Our data indicate that succinylacetone is an extremely potent competitive inhibitor of ALA dehydratase in human as well as in animal tissues. By using purified preparations of the enzyme from human erythrocytes and mouse and bovine liver, an inhibitor constant ranging from 2 x 10(-7) M to 3 x 10(-7) M was obtained. In cultured hepatocytes, succinylacetone also inhibited ALA dehydratase activity, decreased the cellular content of heme and cytochrome P-450, and greatly potentiated the induction response of ALA synthase to drugs such as phenobarbital, chemicals such as allylisopropylacetamide and 3,5-dicarbethoxy-1,4-dihydrocollidine, and natural steroids such as etiocholanolone. Four patients with hereditary tyrosinemia have been studied and all were found to have greatly depressed levels of erythrocyte ALA dehydratase activity and elevated concentrations of this inhibitor in urine. These findings indicate that tyrosinemia is a disorder of special pharmacogenetic interest because succinylacetone, an abnormal product of the tyrosine metabolic pathway, resulting from the primary gene defect of the disease, profoundly inhibits heme biosynthesis in normal cells through a blockade at the ALA dehydratase level, leading to clinical and metabolic consequences that mimic another genetic disease, AIP.
琥珀酰丙酮（4,6 - 二氧代庚酸）是遗传性酪氨酸血症患者体内产生的一种异常代谢产物，其原因是遗传性的富马酰乙酰乙酸水解酶缺乏。已知患有这种遗传性疾病的患者尿液中会排出过量的δ - 氨基乙酰丙酸（ALA），并且某些患者伴有类似急性间歇性卟啉症（AIP）的临床综合征。为了阐明琥珀酰丙酮与血红素生物合成途径的关系，我们研究了这种代谢产物对培养的禽肝细胞中细胞血红素含量以及从正常人红细胞、小鼠和牛肝脏中纯化的ALA脱水酶活性的影响。我们的数据表明，琥珀酰丙酮在人和动物组织中都是ALA脱水酶的一种极强的竞争性抑制剂。通过使用从人红细胞、小鼠和牛肝脏中纯化的酶制剂，获得的抑制常数范围为2×10^(-7) M至3×10^(-7) M。在培养的肝细胞中，琥珀酰丙酮还抑制ALA脱水酶活性，降低血红素和细胞色素P - 450的细胞含量，并极大地增强了ALA合酶对诸如苯巴比妥等药物、烯丙基异丙基乙酰胺和3,5 - 二乙氧羰基 - 1,4 - 二氢可力丁等化学物质以及诸如本胆烷醇酮等天然类固醇的诱导反应。对四名遗传性酪氨酸血症患者进行了研究，发现他们的红细胞ALA脱水酶活性水平均大幅降低，且尿液中这种抑制剂的浓度升高。这些发现表明，酪氨酸血症是一种具有特殊药物遗传学意义的疾病，因为琥珀酰丙酮作为酪氨酸代谢途径的异常产物，由该疾病的原发性基因缺陷产生，通过在ALA脱水酶水平的阻断，深刻抑制正常细胞中的血红素生物合成，导致模仿另一种遗传性疾病AIP的临床和代谢后果。
