Freeman S J, Lloyd J B
Chem Biol Interact. 1986 May;58(2):149-60. doi: 10.1016/s0009-2797(86)80094-1.
Suramin (250 mg/kg) and sodium aurothiomalate (100 mg/kg) both induced congenital malformations in the offspring following treatment of pregnant rats at either 8.5 or 9.5 days of gestation. Conceptuses from 9.5-day pregnant rats were cultured for 48 h in homologous serum to which either suramin or sodium aurothiomalate was added for the final 6 h. The presence of suramin up to 5 mg/ml had no effect on the protein content of yolk sacs at harvesting, but at 10 mg/ml caused a significant decrease. In contrast sodium aurothiomalate increased the protein content of yolk sacs at harvesting, in a concentration-dependent manner up to 100 micrograms/ml. Neither suramin nor sodium aurothiomalate significantly affected embryo protein content. When 125I-labelled polyvinylpyrrolidone was added to the culture serum for the final 6 h of culture, radioactivity was found in the yolk sac at harvesting, but not in the embryo. When suramin (2-10 mg/ml) was present for the final 6 h of culture, the quantity of radioactivity measured in the yolk sac at harvesting was significantly decreased in a concentration-dependent manner. No radioactivity was detected in the embryos. Sodium aurothiomalate had no effect on the uptake of 125I-labelled polyvinylpyrrolidone. When rat serum whose proteins were labelled with [3H]leucine was used as culture medium, radioactivity was found in the conceptus (both yolk sac and embryo) at harvesting. Suramin (5 mg/ml), present for the final or penultimate 6 h, significantly decreased the uptake of radioactivity into conceptuses and caused a significant increase in the proportion of the captured radiolabel that was associated with the yolk sac. Sodium aurothiomalate (25 or 500 micrograms/ml) had no effect on the total uptake of radio-label but caused a significant increase in the proportion of total radioactivity captured that was associated with the yolk sac. These data indicate that suramin, by interfering with both the uptake and intralysosomal digestion of protein, and sodium aurothiomalate, by inhibiting digestion of captured protein, disturb the normal pathway of yolk sac-mediated protein utilization with a consequent diminution of the supply of amino acids to the conceptus. The effects of suramin are seen only at high concentration, those of sodium aurothiomalate at much lower concentrations. It is likely that the two drugs exert their teratogenic action by their effects on the yolk sac nutritional pathway with resultant amino acid deprivation of the conceptus at a critical stage of development.
苏拉明（250毫克/千克）和金硫代苹果酸钠（100毫克/千克）在妊娠第8.5天或9.5天对怀孕大鼠进行处理后，均可导致后代出现先天性畸形。将妊娠9.5天大鼠的孕体在同源血清中培养48小时，在最后6小时加入苏拉明或金硫代苹果酸钠。收获时，浓度高达5毫克/毫升的苏拉明对卵黄囊的蛋白质含量没有影响，但在10毫克/毫升时会导致显著下降。相比之下，金硫代苹果酸钠在收获时会增加卵黄囊的蛋白质含量，在浓度高达100微克/毫升时呈浓度依赖性增加。苏拉明和金硫代苹果酸钠均未显著影响胚胎蛋白质含量。在培养的最后6小时向培养血清中加入125I标记的聚乙烯吡咯烷酮，收获时在卵黄囊中发现放射性，但在胚胎中未发现。在培养的最后6小时加入苏拉明（2 - 10毫克/毫升）时，收获时在卵黄囊中测得的放射性量以浓度依赖性方式显著降低。在胚胎中未检测到放射性。金硫代苹果酸钠对125I标记的聚乙烯吡咯烷酮的摄取没有影响。当使用用[3H]亮氨酸标记蛋白质的大鼠血清作为培养基时，收获时在孕体（卵黄囊和胚胎）中均发现放射性。在最后6小时或倒数第二6小时加入5毫克/毫升的苏拉明，会显著降低放射性进入孕体的摄取量，并导致与卵黄囊相关的捕获放射性标记比例显著增加。金硫代苹果酸钠（25或500微克/毫升）对放射性标记的总摄取量没有影响，但会导致与卵黄囊相关的捕获总放射性比例显著增加。这些数据表明，苏拉明通过干扰蛋白质的摄取和溶酶体内消化，以及金硫代苹果酸钠通过抑制捕获蛋白质的消化，扰乱了卵黄囊介导的蛋白质利用的正常途径，从而导致向孕体供应的氨基酸减少。苏拉明的作用仅在高浓度时可见，金硫代苹果酸钠的作用在低得多的浓度时可见。这两种药物可能通过其对卵黄囊营养途径的影响，在发育的关键阶段导致孕体氨基酸缺乏，从而发挥致畸作用。
