The mechanism by which peroxisome proliferators increase cell replication and cause liver tumors in rodents remains unknown. When activated, Kupffer cells, the resident hepatic macrophages, release a variety of mitogenic stimuli that could theoretically increase cell proliferation in nearby hepatocytes. Therefore, in the present study we evaluated the effect of two potent peroxisome proliferators, nafenopin and WY-14,643, on Kupffer cell activation in vivo. Kupffer cell phagocytosis was determined continuously by monitoring rates of colloidal carbon uptake in the isolated, perfused liver after drug treatment in vivo. In the absence of peroxisome proliferators, colloidal carbon increased rates of oxygen uptake from 88 +/- 10 to 110 +/- 11 mumol/g/h. Livers from rats treated with either nafenopin (2-24 h) or WY-14,643 (24 h) were perfused for approximately 15 min with Krebs-Henseleit buffer and then with buffer containing colloidal carbon (2 mg/ml). Five h after nafenopin treatment (100 mg/kg i.g.), basal rates of colloidal carbon uptake of 136 +/- 12 mg/g/h were increased to 188 +/- 12 and remained elevated after 24 h (203 +/- 3 mg/g/h). Nafenopin also increased rates in a dose-dependent manner (one-half-maximal response, approximately 75 mg/kg). Similarly, WY-14,643 elevated rates of colloidal carbon uptake 1.8-fold over controls. Functional parameters of Kupffer cells were also affected. For example, WY-14,643 increased plasma nitrite significantly. This study demonstrates clearly that nafenopin and WY-14,643 activate Kupffer cell phagocytosis, suggesting a role for cell-to-cell communication in the stimulation of cell replication by peroxisome proliferators.