McMillan D C, Freeman J P, Hinson J A
Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, Arkansas 72079.
Toxicol Appl Pharmacol. 1990 Mar 15;103(1):90-101. doi: 10.1016/0041-008x(90)90265-v.
Methemoglobinemia produced by exposure to the herbicide propanil (3,4-dichloropropionanilide) is thought to be mediated by toxic metabolites formed during the hepatic clearance of the parent compound. We examined the metabolism of propanil and 3,4-dichloroaniline in rat liver microsomes to identify metabolites that may be involved in propanil-induced methemoglobinemia. The major pathway of propanil metabolism in microsomal incubations was acylamidase-catalyzed hydrolysis to 3,4-dichloroaniline. The reaction did not require NADPH, and was inhibited by the acylamidase inhibitors paraoxon and sodium fluoride. Oxidized metabolites were isolated by high-performance liquid chromatography, and identified as 2'-hydroxypropanil and 6-hydroxypropanil by comparison of their mass and nuclear magnetic resonance spectra to those of synthetic standards. Major microsomal metabolites of 3,4-dichloroaniline were 6-hydroxy-3,4-dichloroaniline and N-hydroxy-3,4-dichloroaniline. Both N-hydroxy-3,4-dichloroaniline and 6-hydroxy-3,4-dichloroaniline directly oxidized hemoglobin in rat erythrocyte suspensions in a concentration-dependent manner; however, the potency of N-hydroxy-3,4-dichloroaniline was at least an order of magnitude greater than that of 6-hydroxy-3,4-dichloroaniline.
接触除草剂敌稗（3,4 - 二氯丙酰替苯胺）所产生的高铁血红蛋白血症被认为是由母体化合物在肝脏清除过程中形成的有毒代谢产物介导的。我们研究了敌稗和3,4 - 二氯苯胺在大鼠肝脏微粒体中的代谢情况，以确定可能参与敌稗诱导的高铁血红蛋白血症的代谢产物。在微粒体孵育中，敌稗代谢的主要途径是酰胺酶催化水解生成3,4 - 二氯苯胺。该反应不需要NADPH，并受到酰胺酶抑制剂对氧磷和氟化钠的抑制。通过高效液相色谱法分离出氧化代谢产物，并通过将其质谱和核磁共振光谱与合成标准品的光谱进行比较，鉴定为2'-羟基敌稗和6 - 羟基敌稗。3,4 - 二氯苯胺的主要微粒体代谢产物是6 - 羟基 - 3,4 - 二氯苯胺和N - 羟基 - 3,4 - 二氯苯胺。N - 羟基 - 3,4 - 二氯苯胺和6 - 羟基 - 3,4 - 二氯苯胺都以浓度依赖的方式直接氧化大鼠红细胞悬液中的血红蛋白；然而，N - 羟基 - 3,4 - 二氯苯胺的效力比6 - 羟基 - 3,4 - 二氯苯胺至少高一个数量级。
