Modulation of gamma-glutamyltranspeptidase in normal rat hepatocytes in culture by cell density, epidermal growth factor and agents which alter cell differentiation.

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To help clarify whether elevation of gamma-glutamyltranspeptidase (GGT) in hepatocytes is associated with particular pattern(s) of liver differentiation, adult rat hepatocytes in primary culture were maintained for up to 5 days under conditions considered to alter differentiation in liver or other cells: basal GGT activity in untreated cultures and inducibility of the enzyme by known inducers such as dexamethasone, p,p'-dichlorodiphenyltrichloroethane or pregnenolone 16 alpha-carbonitrile were measured. Basal and induced GGT activities were maximal in confluent cultures and declined with decreasing cell density, an effect probably mediated by cell contact rather than factors in the culture medium. Opposite effects of cell density on GGT and DNA synthesis suggest that increased GGT activity is not linked with growth. Epidermal growth factor (EGF) increased basal GGT and augmented the action of xenobiotic inducers in lower density cultures, giving GGT activities approaching the levels in confluent cells. EGF had no effect on confluent cultures. Activators of protein kinase C such as tetradecanoyl phorbol acetate had significant but small inducing effects on GGT. Agents including all-trans retinoic acid, butyrate and dimethylsulfoxide which are considered to favour terminal differentiation in many cell types, all partly blocked induction of GGT by dexamethasone, EGF or xenobiotics. The results are consistent with (but do not prove) the view that elevated GGT activity may be associated with liver phenotype(s) distinct from terminal differentiation but not necessarily linked with growth.