Bogdanffy Matthew S
DuPont Haskell Laboratory, E. I. du Pont de Nemours and Co., Inc., P.O. Box 50, Newark, Delaware 19714, USA.
Toxicol Sci. 2002 Apr;66(2):320-6. doi: 10.1093/toxsci/66.2.320.
Cancerbioassays have demonstrated the carcinogenic activity of vinyl acetate in rodents. Tumors appear only at the site of contact and mechanistic data suggest that the carcinogenic mechanism involves carboxylesterase-mediated metabolism of vinyl acetate to acetic acid. It has been hypothesized that intracellular formation of acetate causes a reduction of intracellular pH (pH(i)) at noncytotoxic levels, but that prolonged exposure to reduced pH(i) is cytotoxic and/or mitogenic and drives proliferative responses. Coupled with exposure to metabolically formed acetaldehyde at high administered concentrations, nonlinear dose-response curves for epithelial tumors are produced. Freshly isolated rat hepatocytes were used as a model system to test the concept that exposure of cells to vinyl acetate causes a reduction in pH(i). Quantitative fluorescence imaging ratio microscopy showed that exposure of hepatocytes to vinyl acetate concentrations ranging from 10 to 1000 microM caused rapid and sustained reductions of approximately 0.03 to 0.65 pH units. Cellular acidification was rapidly reversed to control pH(i) upon removal of vinyl acetate. There was minimal accumulation of protons during the exposure period, as suggested by minor differences in pH(i) of cells with or without prior exposure to vinyl acetate. The effect of vinyl acetate on pH(i) was attenuated by prior exposure to the carboxylesterase inhibitor bis(p-nitrophenyl)phosphate. These results support the concept that intracellular acidification is a sentinel pharmacodynamic response of cells to vinyl acetate exposure and that pH(i) is an appropriate metric dose for use in quantitative risk assessments of cancer and noncancer human health risk assessment.
癌症生物测定已证明醋酸乙烯酯在啮齿动物中的致癌活性。肿瘤仅出现在接触部位，且机制数据表明致癌机制涉及羧酸酯酶介导的醋酸乙烯酯代谢为乙酸。据推测，在无细胞毒性水平下，细胞内乙酸的形成会导致细胞内pH值（pH(i)）降低，但长时间暴露于降低的pH(i)会产生细胞毒性和/或促有丝分裂作用，并引发增殖反应。再加上在高给药浓度下接触代谢形成的乙醛，会产生上皮肿瘤的非线性剂量反应曲线。新鲜分离的大鼠肝细胞被用作模型系统，以测试细胞暴露于醋酸乙烯酯会导致pH(i)降低这一概念。定量荧光成像比率显微镜显示，肝细胞暴露于10至1000微摩尔浓度的醋酸乙烯酯会导致pH值迅速且持续降低约0.03至0.65个单位。去除醋酸乙烯酯后，细胞酸化迅速恢复到对照pH(i)。在暴露期间质子积累极少，这从有无预先暴露于醋酸乙烯酯的细胞的pH(i)微小差异可以看出。预先暴露于羧酸酯酶抑制剂双（对硝基苯基）磷酸酯会减弱醋酸乙烯酯对pH(i)的影响。这些结果支持以下概念：细胞内酸化是细胞对醋酸乙烯酯暴露的一种前哨药效学反应，且pH(i)是用于癌症和非癌症人类健康风险评估的定量风险评估的合适剂量指标。
