Chen Y, Saito H, Matsuki N
Department of Chemical Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
Life Sci. 1997;60(4-5):253-61. doi: 10.1016/s0024-3205(96)00625-x.
Ethanol-induced emesis were investigated using Suncus murinus and the emetogenic mechanisms of ethanol were compared with those of cisplatin. Intraperitoneal injection of ethanol caused dose-dependent emesis with ED50 value of 22.3% (v/v) when injection volume was adjusted to 4 ml/kg. Intraperitoneal and subcutaneous injection of acetaldehyde also caused dose-dependent emesis (ED50 = 3.5% (v/v) with an extremely shorter latency (6% i.p.: 1.0 +/- 0.3 min cf. 40% ethanol: 13.0 +/- 1.9 min). Neither ethanol nor acetaldehyde caused emetic responses when injected intracerebroventricularly. Pretreatment with disulfiram, an inhibitor of liver aldehyde dehydrogenase, potentiated the emetogenic effects of ethanol. Surgical abdominal vagotomy, which blocks cisplatin-induced emesis completely, did not prevent ethanol-induced emesis. 5-HT3 receptor antagonists, which also cause complete inhibition of cisplatin-induced emesis, did not affect the responses. However, ethanol-induced emesis was prevented by the pretreatment with 8-hydroxy-2-(di-n-propylamino)tetrarin hydrobromide (8-OH-DPAT) and N-(2-mercaptopropionyl)-glycine (MPG) dose-dependently. The tackykinin NK1 receptor antagonist (+)-(2S, 3S)-3-(2-methoxybenzylamino)-2-phenyl-piperidine (CP-99,994) also attenuated ethanol-induced emesis. Taken together, these results suggest that 1) acetaldehyde is probably responsible for ethanol-induced emesis, 2) active site for ethanol maybe peripheral, 3) ethanol-induced emesis is mediated by free radicals, and 4) mechanism of ethanol-induced emesis and that caused by cisplatin are different in many respects, although in some they are similar and that the precise pathways remain to be identified. Therefore, the tolerance to emetogenic effects of cisplatin in alcoholic patients cannot be explained as a simple cross desensitization of the pathway.
利用麝鼩研究了乙醇诱导的呕吐，并将乙醇的致吐机制与顺铂的致吐机制进行了比较。当腹腔注射体积调整为4 ml/kg时，腹腔注射乙醇会引起剂量依赖性呕吐，半数有效剂量（ED50）值为22.3%（v/v）。腹腔注射和皮下注射乙醛也会引起剂量依赖性呕吐（ED50 = 3.5%（v/v），潜伏期极短（腹腔注射6%：1.0±0.3分钟，相比之下40%乙醇：13.0±1.9分钟）。脑室内注射乙醇或乙醛均未引起呕吐反应。用肝脏醛脱氢酶抑制剂双硫仑预处理可增强乙醇的致吐作用。完全阻断顺铂诱导呕吐的腹部迷走神经切断术并不能预防乙醇诱导的呕吐。同样能完全抑制顺铂诱导呕吐的5-羟色胺3（5-HT3）受体拮抗剂对该反应没有影响。然而，用氢溴酸8-羟基-2-（二正丙基氨基）四氢化萘（8-OH-DPAT）和N-（2-巯基丙酰基）-甘氨酸（MPG）预处理可剂量依赖性地预防乙醇诱导的呕吐。速激肽NK1受体拮抗剂（+）-（2S，3S）-3-（2-甲氧基苄基氨基）-2-苯基哌啶（CP-99,994）也可减轻乙醇诱导的呕吐。综上所述，这些结果表明：1）乙醛可能是乙醇诱导呕吐的原因；2）乙醇的作用位点可能在周围；3）乙醇诱导的呕吐是由自由基介导的；4）乙醇诱导呕吐的机制与顺铂诱导呕吐的机制在许多方面不同，尽管在某些方面相似，且确切途径仍有待确定。因此，酒精性患者对顺铂致吐作用的耐受性不能简单地解释为该途径的交叉脱敏。
