Comparative study of the effects of clofibrate, ciprofibrate, WY-14,643, and di-(2-ethylhexyl)-phthalate on liver protein expression in mice

摘要

A comparative study of the effects of clofibrate, ciprofibrate, WY-14,643, and di-(2-ethylhexyl)-phthalate on liver protein expression in mice is described. Two-dimensional gel electrophoresis (2DE) coupled with computer-assisted data analysis was used to examine liver protein expression in untreated mice and in mice exposed to 0.25% clofibrate, 0.025% ciprofibrate, 0.1% (4-chloro-6(2,3-xylidino)-2-pyrimidinylthio)acetic acid (Wy-14,643), or 2.0% di-(2-ethylhexyl)-phthalate (DEHP). To determine the subcellular distribution of the proteins seen in 2DE patterns of liver, preparations of mitochondria, microsomes, peroxisomes, and cytosol were also analyzed by 2DE. At the doses administered, all of these chemicals are known to cause comparable levels of peroxisome proliferation accompanied by an increase in betaoxidation of lipids, and upon prolonged administration, hepatocellular carcinoma. The similarities in biological effects suggest a pleiotropic biochemical response to this group of chemicals. Analysis of 2DE patterns of liver proteins showed that 260 proteins out of a total of approximately 400 were changed in abundance by at least one of the four treatments used. Out of these 260 quantitative protein changes, 45 were comparable in magnitude and direction for all four treatments while the remainder showed treatment-related variability in either magnitude or direction of response. These results indicate, therefore, that against a background of protein changes that are characteristic of the individual chemicals, there is a set of pleiotropic protein changes common to the peroxisome proliferators. The subcellular location of the proteins involved in this pleiotropic response does not appear to be restricted to the peroxisome fraction.