Stoll R E, Blanchard K T, Stoltz J H, Majeska J B, Furst S, Lilly P D, Mennear J H
Stoll & Associates, LLC, Storrs Mansfield, Connecticut 06268, USA.
Toxicol Sci. 2006 Apr;90(2):440-50. doi: 10.1093/toxsci/kfj081. Epub 2005 Dec 22.
Phenolphthalein (800 and 2400 mg/kg/day by gavage and 2400 mg/kg/day by diet) and bisacodyl (800-500, 4000-2000, and 8000 mg/kg/day by gavage) were administered to 15 male and 15 female and 20 male and 20 female p53(+/-) mice respectively for 26 weeks to investigate the potential carcinogenicity of each compound. Toxicokinetic analyses confirmed systemic exposure. p-Cresidine was administered by gavage (400 mg/kg/day) and served as the positive control agent in each study. Dietary phenolphthalein reduced survival in both sexes and early deaths were attributed to thymic lymphoma. No bisacodyl-related neoplasms were observed. Regardless of route of administration to p53(+/-) mice, phenolphthalein but not bisacodyl was unequivocally genotoxic, causing increased micronuclei in polychromatic erythrocytes. In the Syrian hamster embryo (SHE) cell transformation assay, phenolphthalein caused increases in morphologically transformed colonies, thereby corroborating NTP's earlier reports, showing phenolophthalein has potential carcinogenic activity. Bisacodyl was negative in the SHE assay. Results of these experiments confirm an earlier demonstration that dietary phenolphthalein causes thymic lymphoma in p53(+/-) mice and show that (1) phenolphthalein causes qualitatively identical results in this transgenic model regardless of route of oral administration, (2) phenolphthalein shows evidence of micronucleus induction in p53(+/-) mice for up to 26 weeks, (3) phenolphthalein induced transformations in the in vitro SHE assay, and (4) bisacodyl in p53(+/-) mice induces neither drug-related neoplasm, nor micronuclei in polychromatic erythrocytes, and did not induce transformations in the in vitro SHE assay.
分别对15只雄性和15只雌性、20只雄性和20只雌性p53(+/-)小鼠经口灌胃给予酚酞（800和2400毫克/千克/天）和通过饮食给予酚酞（2400毫克/千克/天），并对其经口灌胃给予比沙可啶（800 - 500、4000 - 2000和8000毫克/千克/天），持续26周，以研究每种化合物的潜在致癌性。毒代动力学分析证实了全身暴露。对各研究经口灌胃给予对甲酚定（400毫克/千克/天），并将其作为阳性对照剂。饮食中的酚酞降低了两性的存活率，早期死亡归因于胸腺淋巴瘤。未观察到与比沙可啶相关的肿瘤。无论对p53(+/-)小鼠采用何种给药途径，酚酞具有明确的遗传毒性，可导致多染红细胞微核增加，而比沙可啶则无此作用。在叙利亚仓鼠胚胎（SHE）细胞转化试验中，酚酞导致形态转化菌落增加，从而证实了美国国家毒理学计划（NTP）早期的报告，表明酚酞具有潜在致癌活性。比沙可啶在SHE试验中呈阴性。这些实验结果证实了早期的一项研究结果，即饮食中的酚酞可导致p53(+/-)小鼠发生胸腺淋巴瘤，并表明：（1）无论经口给药途径如何，酚酞在该转基因模型中均产生定性相同的结果；（2）酚酞在p53(+/-)小鼠中显示出长达26周的微核诱导证据；（3）酚酞在体外SHE试验中诱导转化；（4）p(53+/-)小鼠中的比沙可啶既不诱导与药物相关的肿瘤，也不诱导多染红细胞中的微核，且在体外SHE试验中不诱导转化。
