Although liver transplantation has been the subject of intensive investigation, comparatively little is known regarding the effects of this procedure on the metabolism of xenobiotics. The objective of the present study was to examine the effect of orthotopic liver transplantation on rat hepatic, pulmonary, and renal microsomal cytochrome P450 (P450) monooxygenase activity through the use of isozyme-selective substrates. Pulmonary microsomal P450 1A1 dependent 7-ethoxyresorufin O-deethylation (ERFD) activity increased over time in recipient rats, with maximal induction (750% of donor) observed after 21 days. Similarly, ERFD activity in renal microsomes was increased (200% of donor) after 21 days. Both pulmonary and renal microsomal P450 2B dependent 7-pentoxyresorufin O-depentylation (PRFD) activity was decreased (50 and 75% of donor) 1 day after transplantation but was essentially unchanged 3, 7, and 21 days after transplantation. Pulmonary and renal microsomal heme oxygenase activities were not significantly affected by liver transplantation. In contrast, total hepatic microsomal P450 concentrations were decreased maximally (to 45% of donor concentration) 7 days after transplantation and remained low (55% of donor) up to 21 days. Similarly, hepatic P450 1A dependent ERFD and P450 2B dependent PRFD activities were maximally depressed (20 and 25% of donor activities) after 7 days and remained low (75 and 30% of donor) up to 21 days after transplantation. The decreases in rates of hepatic P450 monooxygenation were accompanied by significant increases in microsomal heme oxygenase activity. The data presented in this study suggest the existence of generalized stress responses to inflammation that result in tissue- and isozyme-selective modulation of P450 monooxygenase activity.(ABSTRACT TRUNCATED AT 250 WORDS)