Aw T Y, Jones D P
J Biol Chem. 1982 Aug 10;257(15):8997-9004.
The O2 dependence of cytochrome oxidase, cellular ATP/ADP ratio, and drug sulfation and glucuronidation were studied in isolated hepatocytes to examine secondary biochemical changes of hypoxia related to decreased cytochrome oxidase function. A decrease in cytochrome oxidase function as well as in cellular ATP/ADP ratio occurred at low O2 concentrations and their O2 dependencies gave p50 values of 3.2 and 2.8 microM O2, respectively. Changes in the ATP/ADP ratio corresponded directly with changes in the oxidation-reduction state of cytochrome oxidase. The p50 value for sulfation of acetaminophen (2.5 microM O2) corresponded with the values for ATP/ADP ratio and cytochrome oxidase. Addition of compounds that lowered cellular ATP/ADP ratio caused a corresponding inhibition of sulfation. Selective use of ethionine, an adenosyl-trapping agent, demonstrated that the O2 dependence of sulfation related directly to a decrease in the absolute ATP concentration. The p50 value for glucuronidation (5.2 microM O2) was higher than that for sulfation, but in spite of this difference, glucuronidation also correlated well with cellular ATP/ADP ratio when this ratio was decreased by either O2 limitation or metabolic inhibitors. These results demonstrate that the predominant limitation of drug sulfation and glucuronidation during hypoxia is due to decreased cytochrome oxidase function.
在分离的肝细胞中研究了细胞色素氧化酶的氧依赖性、细胞ATP/ADP比值以及药物硫酸化和葡萄糖醛酸化，以检查与细胞色素氧化酶功能降低相关的缺氧继发性生化变化。在低氧浓度下，细胞色素氧化酶功能以及细胞ATP/ADP比值均降低，它们的氧依赖性分别给出了3.2和2.8 microM O2的p50值。ATP/ADP比值的变化与细胞色素氧化酶的氧化还原状态变化直接相关。对乙酰氨基酚硫酸化的p50值（2.5 microM O2）与ATP/ADP比值和细胞色素氧化酶的值相对应。添加降低细胞ATP/ADP比值的化合物会相应抑制硫酸化。选择性使用腺苷捕获剂乙硫氨酸表明，硫酸化的氧依赖性直接与绝对ATP浓度的降低有关。葡萄糖醛酸化的p50值（5.2 microM O2）高于硫酸化的p50值，但尽管存在这种差异，当通过氧限制或代谢抑制剂降低该比值时，葡萄糖醛酸化也与细胞ATP/ADP比值密切相关。这些结果表明，缺氧期间药物硫酸化和葡萄糖醛酸化的主要限制是由于细胞色素氧化酶功能降低。
