Ebron-McCoy M T, Nichols H P, Andrews J E, Kavlock R J
Perinatal Toxicology Branch, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711, USA.
Teratog Carcinog Mutagen. 1995;15(1):33-42. doi: 10.1002/tcm.1770150105.
Procarbazine (PCZ) is an antineoplastic agent useful in the treatment of Hodgkin's disease, brain tumors, and chronic leukemia. PCZ is dysmorphogenic to developing embryos exposed in vivo or cultured in the serum of PCZ-treated rats. However, embryos directly cultured with PCZ (up to 400 micrograms/ml) or PCZ plus S-9 liver fractions are unaffected. Since intact liver cells provide several advantages over hepatic subcellular fractions for in vitro bioactivation, we exposed rat embryos to PCZ in an embryo/hepatocyte co-culture system. Gestation day (GD) 9.5 rat embryos exposed to 0, 200, 300, or 400 micrograms PCZ/ml in the presence of untreated or phenobarbital induced male rat hepatocytes failed to display toxicity. However, in a companion study GD 9.5 rat embryos cultured in the serum from PCZ-treated rats exhibited developmental deficiencies. Studies have shown that the formation of toxic metabolites can result from glutathione (GSH) conjugation of toxicants in the liver. Therefore, in a second set of experiments, rat embryos were cultured in serum from rats pretreated with two GSH depleters (phorone and buthionine sulfoximine) and subsequently dosed with PCZ. Effects on development were enhanced when embryos were cultured in the serum from PCZ-treated/GSH depleted rats. These data indicate that PCZ requires in vivo activation to be dysmorphogenic and further suggest that the metabolite(s) responsible for procarbazine embryo-toxicity are formed readily under conditions of low GSH levels. This argues against a glutathione conjugate as the ultimate toxicant.
丙卡巴肼（PCZ）是一种抗肿瘤药物，可用于治疗霍奇金病、脑肿瘤和慢性白血病。PCZ对体内暴露或在经PCZ处理的大鼠血清中培养的发育胚胎具有致畸作用。然而，直接用PCZ（高达400微克/毫升）或PCZ加S-9肝组分培养的胚胎未受影响。由于完整的肝细胞在体外生物活化方面比肝亚细胞组分具有几个优势，我们在胚胎/肝细胞共培养系统中将大鼠胚胎暴露于PCZ。在未处理或苯巴比妥诱导的雄性大鼠肝细胞存在的情况下，妊娠第9.5天的大鼠胚胎暴露于0、200、300或400微克PCZ/毫升时未显示毒性。然而，在一项配套研究中，在经PCZ处理的大鼠血清中培养的妊娠第9.5天的大鼠胚胎表现出发育缺陷。研究表明，有毒代谢物的形成可能源于肝脏中谷胱甘肽（GSH）与毒物的结合。因此，在第二组实验中，将大鼠胚胎在经两种GSH消耗剂（佛尔酮和丁硫氨酸亚砜胺）预处理并随后给予PCZ的大鼠血清中培养。当胚胎在经PCZ处理/ GSH耗尽的大鼠血清中培养时，对发育的影响增强。这些数据表明，PCZ需要体内活化才具有致畸性，并进一步表明，在低GSH水平条件下，容易形成负责丙卡巴肼胚胎毒性的代谢物。这与谷胱甘肽结合物作为最终毒物的观点相悖。
