Pharmaceutical agents known to produce disulfiram-like reaction: Effects on hepatic ethanol metabolism and brain monoamines
Pharmaceutical agents known to produce disulfiram-like reaction: Effects on hepatic ethanol metabolism and brain monoamines
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DOI：
10.1080/10915810701583010
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发表时间：
2007-01-01
影响因子：
2.2
通讯作者：
Marselos, Marios
中科院分区：
文献类型：
--
作者：
Karamanakos, Petros N.;Pappas, Periklis;Marselos, Marios
一些药物制剂产生乙醇不耐受，这通常被描述为双硫仑样反应。与双硫仑的情况一样，潜在的机制被认为是乙醛在血液中的积累，这是由于肝醛脱氢酶的抑制。本研究将氯霉素、呋喃唑酮、甲硝唑和奎纳克宁（据报道可产生双硫仑样反应）和双硫仑分别给予Wistar大鼠，测定其肝脏乙醇脱氢酶和醛脱氢酶（1A1和2）的活性。Western blot检测醛脱氢酶2的表达，同时检测脑单胺水平。最后，对经双硫仑、氯霉素或阿奎宁预处理的大鼠进行乙醇处理后的血液乙醛评估。二硫仑、氯霉素和呋喃唑酮对乙醛脱氢酶2的活性有抑制作用，甲硝唑和奎宁对乙醛脱氢酶2的活性无抑制作用。此外，虽然众所周知的甲硝唑，喹那卡因也没有增加乙醇给药后的血液乙醛。醛脱氢酶2蛋白表达不受影响。有趣的是，除了双硫仑外，所有使用的物质都增加了大脑血清素的水平。根据我们的研究结果，甲硝唑和喹那宁不会产生典型的双硫仑样反应，因为它们不会抑制肝醛脱氢酶，也不会增加血液中的乙醛。此外，所有被测试的药物都具有增强脑血清素的共同特性，而乙醇各自的作用已经得到了很好的证实。因此，无论醛脱氢酶是否被抑制，这些药物产生的乙醇不耐受可能是“中毒性血清素综合征”的结果，就像同时使用血清素活性药物的情况一样。
Several pharmaceutical agents produce ethanol intolerance, which is often depicted as disulfiram- like reaction. As in the case with disulfiram, the underlying mechanism is believed to be the accumulation of acetaldehyde in the blood, due to inhibition of the hepatic aldehyde dehydrogenases. In the present study, chloramphenicol, furazolidone, metronidazole, and quinacrine, which are reported to produce a disulfiram- like reaction, as well as disulfiram, were administered to Wistar rats and the hepatic activities of alcohol and aldehyde dehydrogenases (1A1 and 2) were determined. The expression of aldehyde dehydrogenase 2 was further assessed by Western blot analysis, while the levels of brain monoamines were also analyzed. Finally, blood acetaldehyde was evaluated after ethanol administration in rats pretreated with disulfiram, chloramphenicol, or quinacrine. The activity of aldehyde dehydrogenase 2 was inhibited by disulfiram, chloramphenicol, and furazolidone, but not by metronidazole or quinacrine. In addition, although well known for metronidazole, quinacrine also did not increase blood acetaldehyde after ethanol administration. The protein expression of aldehyde dehydrogenase 2 was not affected at all. Interestingly, all substances used, except disulfiram, increased the levels of brain serotonin. According to our findings, metronidazole and quinacrine do not produce a typical disulfiram-like reaction, because they do not inhibit hepatic aldehyde dehydrogenase nor increase blood acetaldehyde. Moreover, all tested agents share the common property to enhance brain serotonin, whereas a respective effect of ethanol is well established. Therefore, the ethanol intolerance produced by these agents, either aldehyde dehydrogenase is inhibited or not, could be the result of a "toxic serotonin syndrome," as in the case of the concomitant use of serotonin-active medications.