CIPROFIBRATE REPRESSES ALPHA(2U)-GLOBULIN EXPRESSION IN LIVER AND INHIBITS D-LIMONENE NEPHROTOXICITY

Peroxisome proliferators are a class of compounds which induce hepatom egaly and peroxisome proliferation in liver parenchymal cells. One of the earliest known effects of peroxisome proliferators is the rapid tr anscriptional activation of the genes responsible for the peroxisomal beta-oxidation system in liver. Long term administration of these chem icals to rats and mice results in the development of hepatocellular ca rcinomas. Here we report that mRNA for alpha(2u)-globulin, a rodent ma le specific protein, is markedly reduced or undetectable by Northern b lot analysis of total RNA in the livers of rats treated with ciprofibr ate. This was further confirmed by immunoblot analysis using antibodie s against alpha(2u)-globulin. Nevertheless, immunohistochemical staini ng and in situ hybridization showed respectively the presence of a few cells that contained alpha(2u)-globulin protein and its mRNA. The alp ha(2u)-globulin mRNA reappeared in the liver 2 weeks following the ces sation of ciprofibrate treatment. Feeding of ciprofibrate for two week s followed by simultaneous feeding of ciprofibrate and a nephrotoxic c hemical d-limonene for 5 weeks revealed that ciprofibrate prevented th e renal accumulation of alpha(2u)-globulin and the nephrotoxicity asso ciated with the binding of d-limonene with alpha(2u)-globulin.