On the factors influencing the individual variation in gamma glutamyltransferase induction.

Enzyme induction is a phenomenon that describes increased microsomal enzyme synthesis caused by the administration of enzyme inducing substances. In order to avoid the disadvantages of enzyme induction it is helpful to have a simple and reliable indicator of microsomal enzyme activity in patients exposed to enzyme inducing drugs. Measurement of serum gamma glutamyl- transferase (gammaGT) activity is the most common indirect method of assessing the phenomenon since serum is easily obtainable and assay methods are readily available. However previous studies of the measurement of serum gammaGT activity as an index of microsomal enzyme induction have been contradictory. This study investigates factors that may influence the individual variations of gammaGT activity in response to the administration of anticonvulsants. Ethical and practical considerations permitted only limited studies to be performed on epileptic patients taking anticonvulsant drug therapy. However a series of extensive investigations involving dietary factors and drug manipulations were conducted on male wistar rats. The factors chosen were known to affect drug metabolism, enzyme induction or protein synthesis. The process of the effects of the dietary factors on induction of gammaGT by phenobarbitone were studied using anatomical, biochemical, histological and electron microscopic techniques. The study showed that the age and sex of the patients, choice of drugs, daily drug dose and duration of therapy may influence the induction of gammaGT activity. The results also showed that administration of phenobarbitone to rats causes a marked but temporary decrease in hepatic glutathione concentration followed by the induction of gammaGT. It was also demonstrated that the dietary factors markedly affect the induction of gammaGT by phenobarbitone. Evidence is presented to indicate that both polyunsaturated fat and proteins potentiate gammaGT induction at the glutathione level whilst carbohydrate and folic acid inhibit at the cyclic AMP level. Evidence from both the clinical and experimental results suggests that gammaGT is a reasonable indicator of microsomal enzyme induction if these factors are taken into account.