KUPFFER CELLS ARE CAUSALLY RESPONSIBLE FOR THE MITOGENIC EFFECT OF PEROXISOME PROLIFERATORS

WY-14 643 [4-chloro-6-(2,3-xylidino)pyrimidinylthio-acetic acid] is a web-known non-genotoxic carcinogen and peroxisome proliferator that ca uses liver cancer in rodents by unknown mechanisms, Its ability to sus tain elevated rates of hepatocyte DNA synthesis is most likely pivotal in the ultimate development of tumors, The source of this mitogenic s timulus following treatment of rats,vith WY-14 643 has been hypothesiz ed to be Kupffer cells, the resident hepatic macrophages, since they a re activated by peroxisome proliferators ill vivo. Therefore, these st udies were designed to determine if Kupffer cells are causally respons ible for WY-14 643-induced increases in hepatocyte DNA synthesis irt v ivo, WY-14 643 (100 mg/kg) increased DNA synthesis 8-fold 24 h after t reatment; however, inactivation of Kupffer cells with methyl palmitate , a non-hydrolyzable fatty acid ester and known Kupffer cell inhibitor , completely prevented the mitogenic effect of WY-14 643, On the other hand, the ability of WY-14 643 to induce peroxisomes was not affected by methyl palmitate, These data demonstrate that induction of peroxis omes is not dependent on factors from Kupffer cells and support the id ea that stimulation of DNA synthesis and induction of peroxisomes occu r via distinct mechanisms, Additionally, WY-14 643 increased liver mRN A transcripts of the hepatocyte mitogen tumor necrosis factor alpha (T NF alpha) more than twofold, This increase was also prevented by inact ivating Kupffer cells with methyl palmitate, Therefore, it is conclude d that Kupffer cells are causally responsible for WY-14 643-induced in creases in hepatocyte DNA synthesis most likely by increasing producti on of TNF alpha, a hepatic mitogen.