Exogenous epidermal growth factor (EGF) markedly increases the in vivo uptake of glutamine by small intestine during total parenteral nutrition (TPN). Since glutamine is the major oxidative fuel for the small intestine and is synthesized mainly in skeletal muscle, we investigated whether EGF would induce changes in the activity of the enzymes that mediate glutamine degradation (glutaminase) and synthesis (glutamine synthetase) in the two tissues. Male Sprague Dawley rats were randomized into three groups: group I (chow) were fed rat chow and water and libitum, group II (TPN) received a standard formula of TPN, and group III (TPN-EGF) received the same TPN as group II and injections of EGF (0.1 microgram/ gm body weight (bw)) subcutaneously twice daily. TPN was given for 2 wk; when EGF was administered along with TPN, the glutaminase activity of intestinal mucosa and the glutamine synthetase activity of skeletal muscle were increased, respectively, by 25% and 24% (P < 0.05, versus TPN group). These data suggest a mechanism whereby EGF enhances the intestinal utilization of glutamine by changing the activities of glutamine metabolic enzymes in the small intestine and skeletal muscle during TPN.