Andrews J E, Ebron-McCoy M, Copeland F, Glennon J J
Developmental Toxicology Division, USEPA, Research Triangle Park, North Carolina 27711.
Toxicol Appl Pharmacol. 1994 Jun;126(2):260-6. doi: 10.1006/taap.1994.1115.
Serum from procarbazine (PCZ)-treated rats is dysmorphogenic to rat embryos cultured in vitro, but PCZ is not effective when added directly to culture medium, even with an exogenous metabolizing system. Methylazoxyprocarbazine (MPCZ) is a metabolite which we have identified by HPLC in the dysmorphogenic serum of PCZ-treated rats. PCZ, MPCZ, and benzylazoxyprocarbazine (BPCZ, an isomer of MPCZ) were tested in rat whole embryo culture to determine their effects on embryo development. The parent compound, PCZ, produced no effect on embryo growth or development at concentrations up to 200 micrograms/ml. MPCZ proved to be the most potent of the agents tested. There was significant embryo lethality at concentrations of > or = 10 micrograms/ml while 25 micrograms/ml had significantly reduced embryonic developmental score (DEVS), and 35 micrograms/ml reduced DEVS, head length, and somite number. There was 89% embryo lethality at the 50 micrograms/ml exposure level. At concentrations > 5 micrograms/ml, there were significant increases in anomalies, primarily, failure of neural tube closure, erratic neural seam, and microcephaly. In contrast, BPCZ produced embryo lethality and reductions in DEVS only at 100 micrograms/ml. These data suggest that MPCZ, which has been identified in PCZ-treated rat serum, may be the proximate dysmorphogenic metabolite of PCZ.
来自丙卡巴肼（PCZ）处理大鼠的血清对体外培养的大鼠胚胎具有致畸作用，但即使添加外源性代谢系统，将PCZ直接添加到培养基中也无效。甲基偶氮氧丙卡巴肼（MPCZ）是一种代谢产物，我们已通过高效液相色谱法在PCZ处理大鼠的致畸血清中鉴定出该物质。在大鼠全胚胎培养中测试了PCZ、MPCZ和苄基偶氮氧丙卡巴肼（BPCZ，MPCZ的异构体）对胚胎发育的影响。母体化合物PCZ在浓度高达200微克/毫升时对胚胎生长或发育没有影响。MPCZ被证明是所测试试剂中最有效的。浓度≥10微克/毫升时有显著的胚胎致死率，而25微克/毫升时胚胎发育评分（DEVS）显著降低，35微克/毫升时DEVS、头长和体节数均降低。在50微克/毫升的暴露水平下有89%的胚胎致死率。浓度>5微克/毫升时，异常情况显著增加，主要是神经管闭合失败、神经缝不规则和小头畸形。相比之下，BPCZ仅在100微克/毫升时产生胚胎致死率并降低DEVS。这些数据表明，在PCZ处理的大鼠血清中已鉴定出的MPCZ可能是PCZ直接的致畸代谢产物。
