Altered regulation of mammalian hepatic heme biosynthesis and urinary porphyrin excretion during prolonged exposure to sodium arsenate.
Altered regulation of mammalian hepatic heme biosynthesis and urinary porphyrin excretion during prolonged exposure to sodium arsenate.
复制标题
长期接触砷酸钠期间，哺乳动物肝血红素生物合成和尿卟啉排泄的调节发生改变。
DOI：
10.1016/0041-008x(78)90015-7
复制
发表时间：
1978
影响因子：
3.8
通讯作者：
B. Fowler
中科院分区：
文献类型：
--
作者：
J. S. Woods;B. Fowler
连续长时间暴露于砷酸钠在20，40，或85 ppm的饮用水导致抑制肝δ-氨基乙酰丙酸（ALA）合成酶和血红素合成酶，第一个和最后一个酶在血红素生物合成，分别在大鼠和小鼠。ALA合成酶在40 ppm时最大抑制至约80%的控制值，在这两个物种，而血红素合成酶活性最大降低至63和75%的控制在85 ppm的大鼠和小鼠，分别。血红素生物合成中的第三种酶尿卟啉原I合成酶在小鼠中的所有剂量下均增加，而第二种血红素生物合成途径酶ALA脱氢酶在两个物种中均未改变。与此同时，尿卟啉浓度升高多达12倍，粪卟啉多达9倍，在大鼠的控制值。在小鼠中观察到类似的卟啉排泄升高模式。相反，细胞色素氧化酶或细胞色素P-450的活性，线粒体和微粒体血红素蛋白功能的指标，分别没有观察到变化。这些结果表明，长期暴露于低水平的砷导致肝血红素生物合成途径酶的选择性改变，伴随着尿卟啉浓度的增加。这些变化，其独特的特点是尿卟啉的主要增加粪卟啉浓度，发生独立的肝血红素蛋白功能的变化，因此可以作为一个特定的指标中毒前砷暴露。
Continuous prolonged exposure to sodium arsenate at 20, 40, or 85 ppm in the drinking water resulted in depression of hepatic δ-aminolevulinic acid (ALA) synthetase and heme synthetase, the first and last enzymes in heme biosynthesis, respectively, in both rats and mice. ALA synthetase was maximally depressed to approximately 80% of control values at 40 ppm in both species, whereas heme synthetase activity was maximally decreased to 63 and 75% of control at 85 ppm in rats and mice, respectively. Uroporphyrinogen I synthetase, the third enzyme in heme biosynthesis, was increased at all doses in the mouse, whereas ALA dehydratase, the second heme biosynthetic pathway enzyme, was unaltered in either species. Concomitantly, urinary uroporphyrin concentrations were elevated by as much as 12 times, and coproporphyrin by as much as nine times, the control values in the rat. Similar patterns of elevated porphyrin excretion were seen in the mouse. In contrast, no changes were observed in the activities of cytochrome oxidase or cytochrome P-450, indicators of mitochondrial and microsomal hemoprotein function, respectively. These results demonstrate that prolonged exposure to low levels of arsenic results in selective alteration of hepatic heme biosynthetic pathway enzymes, with concomitant increases in urinary porphyrin concentrations. These changes, which are uniquely characterized by a predominant increase in uroporphyrin over coproporphyrin concentrations, occur independently of changes in hepatic hemoprotein function and may thus serve as a specific indicator of pretoxic arsenic exposure.