Effect of phenobarbital and the peroxisome proliferator ciprofibrate on γ‐glutamyltranspeptidase activity and leukotriene C4 concentration in cultured rat hepatocytes

Abstract

Peroxisome proliferators induce hepatocellular carcinomas in rodents by an unknown mechanism. gamma-Glutamyltranspeptidase (GGT), a biochemical marker for identifying putative preneoplastic lesions in the liver, is highly expressed in phenobarbital (PB)-promoted altered hepatic foci but not in those promoted by peroxisome proliferators. One of the substrates of GGT is the eicosanoid LTC4. Because peroxisome proliferators and PB have differing effects on eicosanoid metabolism in vivo, we hypothesized that PB would similarly increase LTC4 concentrations, whereas the peroxisome proliferator ciprofibrate (CIP) would not. Cultured hepatocytes were treated with the peroxisome proliferator ciprofibrate (CIP: 100 and 400 microM) or PB (PB: 0.5 and 2 mM). Competitive radioimmunoassay (RIA) was used to determine the concentration of LTC4 in extracts of cultured hepatocytes. CIP decreased the concentration of LTC4 throughout the culture period, but PB increased the LTC4 concentration. Both doses of CIP significantly inhibited the induction of GGT activity at 48 and 72 hours, whereas PB enhanced GGT activity. We therefore hypothesized that LTC4, a substrate of GGT, may induce GGT activity. LTC4, however, did not enhance GGT activity and inhibited it at very high concentrations. The results of this experiment show that CIP and PB have different effects on GGT activity and LTC4 concentration. LTC4, however, does not induce GGT in cultured hepatocytes.