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.

Comitogenicity of eicosanoids and the peroxisome proliferator ciprofibrate in cultured rat hepatocytes

“…studies (Hong et al, 1995;Leung and Glauert, 19961, the addition of ciprofibrate to the cultures lowered the concentrations of PGEz, PGFza, and LTC, . The addition of eicosanoids in addition to ciprofibrate restored their concentrations (Fig.…”

“…Peroxisome proliferators induce increased expression of several genes, including the peroxisomal P-oxidation pathway and the cytochrome P-450 4A family, which metabolize lipids, including eicosanoids and their precursor fatty acids (Brass and Ruff, 1991;Capdevila et al, 1992). We previously found that the peroxisome proliferator ciprofibrate decreases the concentration of several eicosanoids in rat liver and in cultured hepatocytes, including prostaglandins E, and Fa, (PGE, and PGF2,) and leukotriene C, (LTC,); Hong et al, 1995;Wilson et al, 1995;Leung and Glauert, 1996). The relationship of these decreased eicosanoid concentrations to the development of hepatic tumors is unclear, since promotion…”

In Vitro Induction of Differentiation by Ginsenoside Rh2 in SMMC‐7721 Hepatocarcinoma Cell Line

“…The fact that some hepatoma cells can produce α‐foetoprotein suggests that malignant transformation is frequently associated with a change of cells towards the immature state, which usually corresponds to a certain developmental stage of the foetus. At the same time, the increase of γ‐glutamyl transpeptidase activity and heat‐resistant alkaline phosphatase proportion are the specific properties related with hepatocyte malignancy (Hong et al . 1995; Lu et al .…”

“…The fact that some hepatoma cells can produce a-foetoprotein suggests that malignant transformation is frequently associated with a change of cells towards the immature state, which usually corresponds to a certain developmental stage of the foetus. At the same time, the increase of g-glutamyl transpeptidase activity and heat-resistant alkaline phosphatase proportion are the specific properties related with hepatocyte malignancy (Hong et al 1995;Lu et al 1997), while the increase of alkaline phosphatase activity is the marker of hepatoma differentiation (Asmah et al 1994). Our results show G-Rh 2 markedly increased albumin secretion and alkaline phosphatase activity, while strikingly decreased a-foetoprotein secretion, g-glutamyl transpeptidase activity and heat-resistant alkaline phosphatase proportion.…”