In vitro developmental toxicity of five direct-acting alkylating agents in rodent embryos: structure-activity patterns.
In vitro developmental toxicity of five direct-acting alkylating agents in rodent embryos: structure-activity patterns.
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五种直接作用烷化剂在啮齿动物胚胎中的体外发育毒性：结构-活性模式。
DOI：
10.1002/tera.1420400303
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发表时间：
1989
期刊：
影响因子：
--
通讯作者：
Varnum,M
中科院分区：
文献类型：
--
作者：
Faustman,EM;Kirby,Z;Gage,D;Varnum,M
定性和定量检查了5种直接作用烷化剂在啮齿动物植入后胚胎中产生发育毒性的能力。这些试剂在结构上相关，并且能够将甲基（甲基亚硝基脲，MNU;甲基硝基亚硝基胍，MNNG;甲磺酸甲酯，MMS）或乙基（乙基亚硝基脲，ENU;甲磺酸乙酯，EMS）基团提供给亲核试剂。已知这些试剂的反应性不同。在第10天的体外大鼠胚胎中，单次暴露2小时足以引起胚胎致死率和畸形的剂量依赖性增加。定性而言，在处理的胚胎中报告的胚胎畸形模式与在体内研究中观察到的模式相同，特别是在对中枢神经系统和颅面系统的不良影响方面。从数量上看，这些药物的体外效价顺序为：MNNG > MNU > ENU > MMS > EMS。体内研究报告了不同的效价顺序。在体外，甲基化剂始终比乙基化剂更有效。其他化学性质（如生理条件下的亲核反应性或半衰期）无法解释观察到的效价关系。未来对这些药物的其他化学性质（如特定的烷基化和氨甲酰化反应性）的研究可能会扩大这些初步的结构活性观察。
Five direct‐acting alkylating agents were examined qualitatively and quantitatively for their ability to produce developmental toxicity in rodent postimplantation embryos. These agents were structurally related and were capable of donating either a methyl (methylnitrosourea, MNU; methylnitronitrosoguanidine, MNNG; methyl methanesulfonate, MMS) or ethyl (ethylnitrosourea, ENU; ethyl methanesulfonate, EMS) group to nucleophiles. These agents' reactivities were known to differ. In day 10 rat embryos in vitro a single, 2‐hour exposure was shown to be sufficient to elicit dose‐dependent increases in embryo lethality and malformations. Qualitatively, the patterns of embryo malformations reported in treated embryos paralleled those observed in in vivo studies, especially in regard to adverse effects on central nervous system and craniofacial systems. Quantitatively, the order of potency of these agents in vitro was: MNNG > MNU > ENU > MMS > EMS. In vivo studies reported a different order of potency. In vitro, methylating agents were consistently more potent than ethylating agents. Other chemical properties such as nucleophilic reactivity or half‐life under physiological conditions could not explain observed potency relationships. Future investigation of other chemical properties of these agents such as specific alkylation and carbamylation reactivities may expand these intial structure‐activity observations.