Application of quantitative structure-toxicity relationships for the comparison of the cytotoxicity of 14 p-benzoquinone congeners in primary cultured rat hepatocytes versus PC12 cells

作者：Siraki AG; Chan TS; O'Brien PJ^*

来源：Toxicological Sciences, 2004, 81(1): 148-159.

DOI：10.1093/toxsci/kfh182

• quantitative structure-toxicity relationships
• quinone
• primary rat hepatocytes
• PC12 cell cultures
• ROS formation
• GSH depletion

Quinones are believed to induce their toxicity by two main mechanisms: oxygen activation by redox cycling and alkylation of essential macromolecules. The physicochemical parameters that underlie this activity have not been elucidated, although redox potential is believed to play a significant role. In this study, we have evaluated the cytotoxicity, formation of reactive oxygen species (ROS), and the glutathione (GSH) depleting ability of 14 p-benzoquinone congeners in primary rat hepatocyte and PC 12 cell cultures. All experiments were performed under identical conditions (37degreesC, 5% CO2/air) in 96-well plates. The most cytotoxic quinone was found to be tetrachloro-p-benzoquinone (chloranil), and the least toxic was duroquinone or 2,6-di-tert-butyl-p-benzoquinone. The cytotoxic order varied between the cell types, and in particular, the di-substituted methoxy or methyl p-benzoquinones were particularly more cytotoxic towards PC12 cells. We have derived one- and two-parameter quantitative structure-toxicity relationships (QSTRs) which revealed that the most cytotoxic quinones had the highest electron affinity and the smallest volume. Cytotoxicity did not correlate with the lipophilicity of the quinone. Furthermore, we found that p-benzoquinone cytotoxicity correlated well with hepatocyte ROS formation and GSH depletion, whereas in PC 12 cells, cytotoxicity did not correlate with ROS formation and somewhat correlated with GSH depletion. Hepatocytes had far greater hydrogen peroxide detoxifying capacity than PC12 cells, but PC12 cells contained more GSH/mg protein. Thus, p-benzoquinone-induced ROS formation was greater towards PC12 cells than with hepatocytes. To our knowledge, this is the first QSTR derived for p-benzoquinone cytotoxicity in these cell types and could form the basis for distinguishing certain cell-specific cytotoxic mechanisms.

• 出版日期2004-9