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Inhibition of Cell Proliferation by Ciprofibrate in Glutathione S-Transferase P1-1-positive Rat Hepatic Hyperplastic Nodules¹

Department of Environmental Health, University of Washington, Seattle, Washington 98195

Previous studies have demonstrated that short-term treatment with a peroxisome proliferator (PP) decreased the size and number of genotoxic carcinogen-induced hepatic hyperplastic lesions identified by -glutamyl transpeptidase (GGT) or glutathione S-transferase P1-1 (rGSTP1-1) staining. However, longer-term PP treatment of animals bearing similar hepatic hyperplastic lesions produced an increase in both the size and number of liver tumors. To characterize the hepatic hyperplastic lesions which are inhibited or promoted by PP, a unique double labeling technique was developed to determine the relative rate of cell division (e.g., DNA synthesis) in rGSTP1-1-positive nodules before and after ciprofibrate (Cip) treatment. rGSTP1-1-positive nodules were induced with the Solt-Farber resistance protocol (diethylnitrosamine-2-acetylaminofluorene partial hepatectomy). Eleven weeks after diethylnitrosamine initiation, 3 groups of rats were maintained on a control chow diet or switched to a powdered chow diet containing 0.025% Cip or 0.05% phenobarbital (PB) for the last 8 days of the experiment. A minipump implanted in the abdominal cavity released [methyl-³H]thymidine continuously for 72 h and was then removed prior to Cip or PB treatment. A second minipump was then implanted which released bromodeoxyuridine to the abdominal cavity 5 days after the start of Cip or PB administration and lasted for 72 h until the termination of the experiment. Both the [methyl-³H]thymidine and bromodeoxyuridine labeling indices (LIs) were determined in the same group of cells within individual rGSTP1-1-positive nodules in the right posterior lobes of livers. PB treatment increased both the average number of persistent GGT-positive nodules and the ratio of persistent GGT-positive to rGSTP1-1-positive nodules/cm². In contrast, Cip treatment greatly decreased the average number and area of persistent GGT-positive nodules, as well as the ratio between persistent GGT-positive and rGSTP1-1-positive nodules/cm². Cip treatment also resulted in a 40% decrease in the average LI in the rGSTP1-1-positive nodules. In some rGSTP1-1-positive nodules, the LI was decreased from >40% prior to Cip treatment to <5% afterward, suggesting that Cip treatment interrupted progression in these nodules. Such drastic changes in the LI before and after treatments were not observed in either PB- or vehicle-treated (control) animals. A number of small nodules with a high bromodeoxyuridine LI but with no or very few [methyl-³H]thymidine-labeled nuclei and negative GGT and rGSTP1-1 staining were detected only in the Cip group. These later subtypes of nodules may represent precursors of liver cancers with either negative or positive GGT/rGSTP1-1 phenotype following long-term PP treatment. Thus, Cip treatment resulted in two apparently opposing effects: (a) inhibition of cell division in most established GGT/rGSTP1-1-positive hyperplastic nodules; and (b) promotion of cell division in certain other small GGT/rGSTP1-1-negative lesions. Our data further strengthen the notion that there are fundamental differences between mechanisms of liver tumor promotion by PP and PB.

¹ This work was supported by NIH Grant ES-03933.

² To whom requests for reprints should be addressed, at Department of Environmental Health, SC-34, F-561 HSB University of Washington, Seattle, WA 98195.

Received 11/29/93. Accepted 3/18/94.

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