Relationship between inductions of monooxygenase activity and gamma-glutamyltranspeptidase in rat hepatocyte primary cultures.

The proposition that changes in activity of gamma-glutamyltranspeptidase (GGT) in serum may provide a useful index of the extent of induction of liver drug-metabolizing enzymes by various drugs was examined by comparing control of GGT and monooxygenase activities in cultured hepatocytes. In rat hepatocyte monolayers maintained for up to 5 days the effects of xenobiotics and other factors on cellular GGT activity were compared with effects on a relatively broad measure of drug metabolism, the 7-ethoxycoumarin O-deethylase (ECD) activity of intact cells. A diverse group of drugs including phenobarbital and other barbiturates, diphenylhydantoin, glutethimide, aminopyrine and griseofulvin and the steroids dexamethasone and pregnenolone 16 alpha-carbonitrile were shown to induce both GGT and ECD under comparable culture conditions. Inductions of both activities were potentiated by glucocorticoids and depressed (where tested) by dibutyryl cyclic AMP. Some other hormones or nutrients modulated the activities differently. The magnitude of GGT induction by different drugs did not correlate with relative ECD induction and for several drugs the concentration-dependence of the two effects was different. Interpretation is complicated by the possible contribution of multiple forms of cytochrome P-450 to ECD activity but it seems unlikely that drugs which induce both GGT and drug metabolism do so via a common regulatory mechanism. For such drugs changes in serum GGT could provide only a crude guide to likely changes in drug metabolism. Some compounds including polycyclic hydrocarbons and warfarin induced ECD but had no associated effect on GGT in hepatocytes.