Induction of γ-glutamyl transpeptidase in primary cultures of normal rat hepatocytes by liver tumor promoters and structurally related compounds

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Abstract
Rat hepatocytes maintained for up to 6 days in primary culture were used to test a variety of xenobiotics and steroids for effects on the activity of γ-glutamyl transpepti dase (GGT) in normal cells. In control cultures GGT activity was low and increased slowly with time. When added to cultures for 5 days, a variety of xenobiotics and steroids increased GGT activity to levels 2- to 6-times those of control cultures. Induction of GGT was potentiated for most test compounds by 20-30 nM dexamethasone and diminished by nicotinamide or adenoslne-3′,5′-mono- phosphate. Effective non-genotoxic inducers included phenobarbital and some structurally related compounds, p,p′-dichlorodiphenyltrichloroethane, α and γ-hexachloro cyclohexanes, Aroclor 1254, butyl hydroxytoluene, nafeno-pin, various estrogens, progesterone, pregnenolone carhonitrile and cyproterone acetate. A number of com-pounds including barbituric acid, butyl hydroxyanisole, acetaminophen, saccharin, caffeine, clofibrate and some bile acids failed to induce GGT. Except for 2-acetylaminofluorene and diethylnitrosainine, genotoxic compounds tested did not increase GGT. The results establish that a structurally diverse group of xenobiotics and steroids, many of which are considered to be liver tumour promoters, may directly enhance GGT gene expression in normal hepatocytes. Thus, a variety of compounds used in experimental studies of liver cancer induction as promoters may elevate GGT by mechanism(s) not necessarily related to carcinogenesis.