Study of the ability of phenacetin, acetaminophen, and aspirin to induce cytotoxicity, mutation, and morphological transformation in C3H/10T1/2 clone 8 mouse embryo cells.
Study of the ability of phenacetin, acetaminophen, and aspirin to induce cytotoxicity, mutation, and morphological transformation in C3H/10T1/2 clone 8 mouse embryo cells.
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发表时间：
1989-02
期刊：
影响因子：
11.2
通讯作者：
S. Patierno;N. Lehman;B. Henderson;J. Landolph
中科院分区：
文献类型：
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作者：
S. Patierno;N. Lehman;B. Henderson;J. Landolph
使用止痛化合物乙酰水杨酸（阿司匹林）、非那西丁和对乙酰氨基酚与人类患肾癌的风险增加有关。因此，我们研究了这些化合物在培养的C3 H/10 T1/2克隆8（10 T1/2）小鼠胚胎细胞中诱导细胞毒性、哇巴因耐药性突变和形态转化的能力。所有三种化合物在0.5-mg/ml至2-mg/ml浓度下均具有细胞毒性，如降低的平板接种效率所证明。即使在细胞毒性浓度下，也没有化合物诱导可检测的碱基取代突变对哇巴因抗性。阿司匹林没有诱导形态学转化。非那西丁和对乙酰氨基酚诱导低，但浓度依赖性数量的非典型，弱II型形态转化灶;在等摩尔浓度下，非那西丁是1.1 - 3.0倍，更积极地诱导这些灶。非那西丁和对乙酰氨基酚都不与3-甲基胆蒽共转化，当加入3-甲基胆蒽启动的10T1/2细胞时，两种化合物都不促进细胞转化。通过添加Arochlor-induced仓鼠肝S9组分作为外源性代谢系统，增加了两种化合物的病灶诱导效力。然而，七个假定的代谢物的非那西丁和对乙酰氨基酚，测试-N-羟基非那西丁，对-苯乙啶，对-氨基苯酚，对-亚硝基苯酚，苯醌，乙酰胺，和N-乙酰基-p-benzoquinoneimine-在转化试验中无活性的浓度降低处理细胞的平板接种效率的50%的未处理（对照）细胞的平板接种效率。几个对乙酰氨基酚和非那西丁诱导的病灶进行克隆，扩大到细胞系，并进行了表征。这些细胞系稳定形成II型病灶时，保持在融合2至4周的重建实验与非转化10 T1/2细胞，但是，他们没有表现出显着增加的饱和密度相比，10 T1/2细胞，他们没有生长在软琼脂糖。这些结果表明，高浓度的非那西丁和对乙酰氨基酚的代谢中间体诱导10T1/2小鼠胚胎细胞的非肿瘤性形态转化的频率低。
Use of the analgesic compounds acetylsalicylic acid (aspirin), phenacetin, and acetaminophen has been correlated with increased risk of renal cancer in humans. Hence, we studied these compounds for ability to induce cytotoxicity, mutation to ouabain resistance, and morphological transformation in cultured C3H/10T1/2 clone 8 (10T1/2) mouse embryo cells. All three compounds were cytotoxic from 0.5-mg/ml to 2-mg/ml concentrations as evidenced by decreased plating efficiency. None of the compounds induced detectable base substitution mutations to ouabain resistance even at cytotoxic concentrations. Aspirin did not induce morphological transformation. Both phenacetin and acetaminophen induced low but concentration-dependent numbers of atypical, weak type II morphologically transformed foci; at equimolar concentrations, phenacetin was 1.1- to 3.0-fold more active in inducing these foci. Neither phenacetin nor acetaminophen was cotransforming with 3-methylcholanthrene, and neither compound promoted cell transformation when added to 3-methylcholanthrene-initiated 10T1/2 cells. The focus-inducing potency of both compounds was increased by addition of an Arochlor-induced hamster liver S9 fraction as an exogenous metabolizing system. However, seven putative metabolites of phenacetin and acetaminophen that were tested--N-hydroxyphenacetin, p-phenetidine, p-aminophenol, p-nitrosophenol, benzoquinone, acetamide, and N-acetyl-p-benzoquinoneimine--were inactive in transformation assays at the concentrations reducing plating efficiency of treated cells to 50% of the plating efficiency of nontreated (control) cells. Several acetaminophen- and phenacetin-induced foci were cloned, expanded into cell lines, and characterized. These cell lines stably formed type II foci when maintained at confluence for 2 to 4 wk in reconstruction experiments with nontransformed 10T1/2 cells; however, they did not exhibit significantly increased saturation density compared to 10T1/2 cells, and they did not grow in soft agarose. These results suggest that metabolic intermediates of high concentrations of phenacetin and acetaminophen induce a low frequency of nonneoplastic morphological transformation of 10T1/2 mouse embryo cells.