Hepatic expression of acute-phase protein genes during carcinogenesis induced by peroxisome proliferators

Concern exists regarding peroxisome proliferator (PP) xenobiotic exposure b ecause many PPs are potent hepatocarcinogens in rodents. The mechanism of c arcinogenicity induced by PPs is atypical compared with those of other hepa tocarcinogens in that the former appears to involve alterations in expressi on of PP-activated receptor (PPAR) target genes rather than direct mutageni city. To begin to identify some of these genes, we used differential displa y to compare mRNA expression between hepatic adenomas and adjacent non-tumo r liver from rats fed the potent PP Wy-14643 (WY) for 78 wk. Here, we repor t increased expression of the acute-phase protein (APP) gene alpha-1 antitr ypsin (AT) and decreased expression of alpha 2-urinary globulin in the tumo rs. Similar changes were seen in hepatic adenomas induced by a diethylnitro samine and phenobarbital protocol, indicating a lack of specificity for PP- induced tumors. Additional APP genes, including ceruloplasmin, haptoglobin, beta-fibrinogen, and ctl-acid glycoprotein were also upregulated in WY-ind uced tumors but were downregulated in the livers of rats administered a dif ferent PP for 13 wk. Mice treated with either WY or di(2-ethylhexyl) phthal ate for 3 wk had decreased hepatic AT expression but increased expression o f ceruloplasmin and haptoglobin. PPAR alpha-null mice showed no hepatic APP gene alteration after PP treatment but had higher basal expression than di d wild-type controls. We conclude that PPAR alpha activation by several dif ferent PPs leads to dysregulation of hepatic APP gene expression in rats an d mice. This dysregulation may indicate alterations in cytokine signaling n etworks regulating both APP gene expression and hepatocellular proliferatio n. Mel. Carcinog. 26:226-238, 1999. (C) 1999 Wiley-Liss, Inc.