Lambrecht R W, Sinclair P R, Bement W J, Sinclair J F, Carpenter H M, Buhler D R, Urquhart A J, Elder G H
Veterans Administration, White River Junction, VT 05001.
Biochem J. 1988 Jul 1;253(1):131-8. doi: 10.1042/bj2530131.
The relationship between hepatic uroporphyrin accumulation and uroporphyrinogen decarboxylase (EC 4.1.1.37) activity was investigated in cultured chick-embryo hepatocytes, Japanese quail (Coturnix coturnix japonica) and mice that had been treated with polyhalogenated aromatic compounds. Chick-embryo hepatocytes treated with 3,3',4,4'-tetrachlorobiphenyl accumulated uroporphyrin in a dose-dependent fashion without a detectable decrease in uroporphyrinogen decarboxylase activity when either pentacarboxyporphyrinogen III or uroporphyrinogen III were used as substrates in the assay. Other compounds, such as hexachlorobenzene, parathion, carbamazepine and nifedipine, which have been shown previously to cause uroporphyrin accumulation in these cells, did not decrease uroporphyrinogen decarboxylase activity. Japanese quail treated with hexachlorobenzene for 7-10 days also accumulated hepatic uroporphyrin without any decrease in uroporphyrinogen decarboxylase activity. In contrast, hepatic uroporphyrin accumulation in male C57BL/6 mice treated with iron and hexachlorobenzene was accompanied by a 20-80% decrease in uroporphyrinogen decarboxylase activity, demonstrating that the assay used for uroporphyrinogen decarboxylase, using pentacarboxyporphyrinogen III as substrate, could detect decreased enzyme activity. Our results with chick hepatocytes and quail, showing uroporphyrin accumulation without a decrease in uroporphyrinogen decarboxylase activity, are consistent with a new two-stage model of the uroporphyria: initially uroporphyrinogen is oxidized by a cytochrome P-450-mediated reaction, followed in rodents by a progressive decrease in uroporphyrinogen decarboxylase activity.
在培养的鸡胚肝细胞、日本鹌鹑（日本鹌鹑）和用多卤代芳香化合物处理过的小鼠中，研究了肝脏中尿卟啉积累与尿卟啉原脱羧酶（EC 4.1.1.37）活性之间的关系。用3,3',4,4'-四氯联苯处理的鸡胚肝细胞以剂量依赖的方式积累尿卟啉，当在测定中使用五羧基卟啉原III或尿卟啉原III作为底物时，尿卟啉原脱羧酶活性没有可检测到的降低。其他化合物，如六氯苯、对硫磷、卡马西平和硝苯地平，先前已证明会导致这些细胞中尿卟啉积累，但并未降低尿卟啉原脱羧酶活性。用六氯苯处理7-10天的日本鹌鹑肝脏中也积累了尿卟啉，而尿卟啉原脱羧酶活性没有任何降低。相比之下，用铁和六氯苯处理的雄性C57BL/6小鼠肝脏中尿卟啉的积累伴随着尿卟啉原脱羧酶活性降低20-80%，这表明以五羧基卟啉原III为底物用于尿卟啉原脱羧酶的测定可以检测到酶活性的降低。我们对鸡肝细胞和鹌鹑的研究结果表明，尿卟啉积累而尿卟啉原脱羧酶活性没有降低，这与一种新的迟发性皮肤卟啉症两阶段模型一致：最初尿卟啉原通过细胞色素P-450介导的反应被氧化，随后在啮齿动物中尿卟啉原脱羧酶活性逐渐降低。
