Ramamoorthy J D, Ramamoorthy S, Leibach F H, Ganapathy V
Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta 30912-2100, USA.
Am J Obstet Gynecol. 1995 Dec;173(6):1782-7. doi: 10.1016/0002-9378(95)90427-1.
The use of amphetamine and its derivatives during pregnancy is known to have adverse effects on the outcome of pregnancy. These effects are at least partly a result of impairment of placental function caused by these abusable drugs. We hypothesized that the two monoamine transporters, namely, the serotonin transporter and the norepinephrine transporter, that are expressed in the human placenta are direct targets for these drugs.
The interaction of amphetamine and methamphetamine with human placental serotonin and norepinephrine transporters was examined. Activity of the serotonin transporter was assessed by serotonin uptake in both maternal-facing brush border membrane vesicles isolated from normal term human placentas and in JAR choriocarcinoma cells. Activity of the norepinephrine transporter was assessed by dopamine uptake and nisoxetine binding in placental brush border membrane vesicles.
Amphetamine and methamphetamine are potent inhibitors of the serotonin and norepinephrine transporters expressed in the human placenta. The inhibitory potency of amphetamine is greater than that of methamphetamine. In each case, the S(+)diastereoisomer is more potent than the corresponding R(-)diastereoisomer. The sensitivity of the norepinephrine transporter to inhibition by these drugs is at least two orders of magnitude greater than that of the serotonin transporter. At concentrations known to occur in the plasma of users, these drugs cause a marked inhibition of the norepinephrine transporter.
The results show that the norepinephrine transporter and, to a lesser extent, the serotonin transporter are cellular targets in the human placenta for the abusable drugs amphetamine and methamphetamine.
已知孕期使用苯丙胺及其衍生物会对妊娠结局产生不良影响。这些影响至少部分是由这些可滥用药物导致的胎盘功能受损所致。我们推测，在人胎盘中表达的两种单胺转运体，即5-羟色胺转运体和去甲肾上腺素转运体，是这些药物的直接作用靶点。
检测了苯丙胺和甲基苯丙胺与人胎盘5-羟色胺和去甲肾上腺素转运体的相互作用。通过从足月正常人类胎盘分离的面向母体的刷状缘膜囊泡以及JAR绒毛膜癌细胞中的5-羟色胺摄取来评估5-羟色胺转运体的活性。通过胎盘刷状缘膜囊泡中的多巴胺摄取和奈西立肽结合来评估去甲肾上腺素转运体的活性。
苯丙胺和甲基苯丙胺是人胎盘中表达的5-羟色胺和去甲肾上腺素转运体的强效抑制剂。苯丙胺的抑制效力大于甲基苯丙胺。在每种情况下，S(+)非对映异构体比相应的R(-)非对映异构体更有效。去甲肾上腺素转运体对这些药物抑制的敏感性比对5-羟色胺转运体的敏感性至少高两个数量级。在已知使用者血浆中出现的浓度下，这些药物会导致去甲肾上腺素转运体受到显著抑制。
结果表明，去甲肾上腺素转运体以及在较小程度上5-羟色胺转运体是人胎盘中可滥用药物苯丙胺和甲基苯丙胺的细胞作用靶点。
