Decreased drug metabolism and hepatic cytochrome P-450 levels have been shown previously to occur in rats receiving total parenteral nutrition (TPN) compared to animals receiving the same hyperalimentation solution enterally (TEN). In the present studies, animals received a 7-day infusion of a 25% glucose-2.75% crystalline amino acid solution via a catheter in the jugular vein or stomach; hepatic microsomal levels of four major constitutive cytochromes P-450 were determined subsequently by immunoquantitation and correlated with metabolism of selected substrates biotransformed by these enzymes. TPN resulted in a marked decrease in apoprotein of two constitutive cytochromes P-450, P-450UT-A and P-450PCN-E, compared to TEN experiments (for P-450UT-A, 11.0 +/- 1.8 vs 44.7 +/- 6.5% of total cytochrome P-450 measured by CO-difference spectra, P greater than 0.001; for P-450PCN-E, 15.4 +/- 4.4 vs 30.2 +/- 7.6%, P less than 0.01), but apoprotein levels of two other constitutive cytochromes P-450, P-450PB-C and P-450UT-F, showed relatively little change. Concordant reductions in metabolism of benzphetamine, ethylmorphine and erythromycin were seen in TPN animals. While the mechanisms responsible for these selective changes in the synthesis and function of individual cytochromes P-450 remain to be elucidated, altered gene transcription due to differences in portal blood composition elicited by intravenous versus enteral feeding is a possible hypothesis. These studies also provide information which should be valuable in designing studies to probe further the clinical question of whether TPN induces significant alterations in human drug metabolism.