Effect of dexamethasone on ciprofibrate-induced cell proliferation and peroxisome proliferation.

Peroxisome proliferators cause liver cell proliferation in addition to other pleiotropic effects such as peroxisome proliferation and induction of certain peroxisomal and cytosolic enzymes in liver. Since dexamethasone has been shown to inhibit mitogen-induced liver cell hyperplasia, we examined whether dexamethasone inhibits only cell proliferation without affecting peroxisome proliferation induced by peroxisome proliferators such as ciprofibrate. Livers of rats fed a diet containing ciprofibrate (0.025%) with or without added dexamethasone (0.5 mg or 1 mg/kg diet) for 1 week were evaluated for hepatocyte proliferation and peroxisome proliferation. Dexamethasone administration resulted in abrogation of ciprofibrate-induced cell proliferation as shown by bromodeoxyuridine (BrdU) labeling and mitoses counts. The hepatocyte proliferative index measured after administration of a single dose of BrdU was 18.3 +/- 1.1 and 2.3 +/- 0.7% (p < 0.01) in ciprofibrate and ciprofibrate + dexamethasone treated rats, respectively. With multiple injections of BrdU (daily injections for 7 days) the proliferative index was 225 +/- 10 and 183 +/- 2% (p < 0.02), respectively, in these two groups. Interestingly, whereas the levels of peroxisome proliferator-induced Mr 80,000 polypeptide and catalase and peroxisomal bifunctional enzyme, and the corresponding mRNAs and peroxisome volume density were unaffected. These results show that dexamethasone selectively inhibits only cell proliferation without inhibiting the peroxisome proliferation caused by ciprofibrate. This model should be useful for examining the role of cell proliferation versus oxidative stress in peroxisome proliferator-induced hepatocarcinogenesis.