INHIBITION OF PPAR-ALPHA RXR-ALPHA-MEDIATED DIRECT HYPERPLASIA PATHWAYS DURING GRISEOFULVIN-INDUCED HEPATOCARCINOGENESIS/

Chronic griseofulvin (GF) feeding induces preneoplastic foci followed by hepatocellular carcinoma in the mouse liver. Our previous study sug gested that CF-induced hepatocellular proliferation had a different me chanism from that of peroxisome proliferator (PP)-induced direct hyper plasia. The CF-induced hepatocellular proliferation was mediated throu gh activation of immediate early genes such as Fos, Jun, Myc, and NF k appa B. In contrast, PP-induced direct hyperplasia does not involve ac tivation of any of these immediate early genes. It has been shown that nuclear hormone receptors including peroxisome proliferator activated receptors (PPARs) and retinoid x receptors (RXRs) play important role s in mediating the pleiotropic effects of PPs. To examine the possible roles of PPARs and RXRs during non-PP-induced hepatocellular prolifer ation and the interaction between PP and non-PP-induced proliferation, we have studied the expression of the PPAR and RXR genes in the CF mo del using northern blot hybridizations and gel retardation assays. The data showed that the expression of PPAR alpha and RXR alpha genes was down-regulated in the livers containing preneoplastic nodules and in the liver tumors induced by GF. The mRNA down-regulation was accompani ed by a decrease in the amount of nuclear protein-bound to peroxisome proliferator and retinoic acid responsive elements. Down-regulation wa s also associated with the suppressed expression of the PPAR alpha/RXR alpha target genes (i.e., acyl-Co oxidase and cytochrome P450 4A1) an d the catalase gene. The RXR gamma gene was also down-regulated, but t he RAR alpha, beta, and gamma and PPAR beta and gamma genes were up-re gulated. These results indicated that the hepatocarcinogenesis induced by GF is accompanied by suppression of the PPAR alpha/RXR alpha-media ted direct hyperplasia pathway. The differential expression of these n uclear hormone receptors reveals a new aspect for understanding the in dividual roles and intercommunication of PPAR, RXR, and RAR isoforms i n the liver. (C) 1998 Wiley-Liss, Inc.