Cloning genes responsive to a hepatocarcinogenic peroxisome proliferator chemical reveals novel targets of regulation

To better understand the molecular basis of the hepatocyte proliferation an d induction of hepatocellular adenomas by exposure to peroxisome proliferat or chemicals (PPC), a systematic search for genes modulated by a PPC (WY-14 643) in rat liver was carried out using the differential display technique. The fragments fell into two classes based on the time of initial and maxim al induction by WY-14643. The class I genes (clones 5 and 30) were induced 3 h after a gavage exposure to WY-14643 with maximal expression at 24 h. Th e class II genes (clones 13 and 16) were induced after 24 h with maximal ex pression at 78 weeks. Expression of the class II genes was also increased a fter other treatments that cause cell proliferation. Clone 30 was identifie d as CYP4A2, previously shown to be regulated by PPC. Clone 13 was homologo us to the mouse protein Ii gene, a component of the heterogeneous nuclear r ibonucleoprotein particle important in mRNA splicing. Clone 16 was identifi ed as cyclophilin-A, the receptor for the immunosuppressant drug cyclospori n A. The sequence of clone 5 was unique. These data demonstrate that WY-146 43 increases the levels of a number of never genes that are coordinately re gulated with increases in chronic cell proliferation and fatty acid metabol ism. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.