Ciprofibrate represses α_2u-globulin expression in liver and inhibits d-limonene nephrotoxicity

Peroxisome proliferators are a class of compounds which induce hepatomegaly and peroxisome proliferation in liver parenchymal cells. One of the earliest known effects of peroxisome proliferators is the rapid transcriptional activation of the genes responsible for the peroxisomal β-oxidation system in liver. Long term administration of these chemicals to rats and mice results in the development of hepatocellular carcinomas. Here we report that mRNA for α_2u-globulin, a rodent male specific protein, is markedly reduced or undetectable by Northern blot analysis of total RNA in the livers of rats treated with ciprofibrate. This was further confirmed by immunoblot analysis using antibodies against α_2u-globulin. Nevertheless, immunohistochemical staining and in situ hybridization showed respectively the presence of a few cells that contained α_2U-globulin protein and its mRNA. The α_2u-globulin mRNA reappeared in the liver 2 weeks following the cessation of ciprofibrate treatment. Feeding of ciprofibrate for two weeks followed by simultaneous feeding of ciprofibrate and a nephrotoxic chemical d-limonene for 5 weeks revealed that ciprofibrate prevented the renal accumulation of α_2u-globulin and the nephrotoxicity associated with the binding of d-limonene with α_2u-globulin.