Cj. Sinal et al., LIVER-TRANSPLANTATION INDUCES CYTOCHROME-P450 1A1 DEPENDENT MONOOXYGENASE ACTIVITY IN RAT LUNG AND KIDNEY, Canadian journal of physiology and pharmacology, 73(1), 1995, pp. 146-152
Although liver transplantation has been the subject of intensive inves
tigation, comparatively Little is known regarding the effects of this
procedure on the metabolism of xenobiotics. The objective of the prese
nt 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 substrat
es. Pulmonary microsomal P450 1A1 dependent 7-ethoxyresorufin O-deethy
lation (ERFD) activity increased over time in recipient rats, with max
imal induction (750% of donor) observed after 21 days. Similarly, ERFD
activity in renal microsomes was increased (200% of donor) after 21 d
ays. Both pulmonary and renal microsomal P450 2B dependent 7-pentoxyre
sorufin O-depentylation (PRFD) activity was decreased (50 and 75% of d
onor) 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 transpl
antation. In contrast, total hepatic microsomal P450 concentrations we
re decreased maximally (to 45% of donor concentration) 7 days after tr
ansplantation 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 day
s and remained low (75 and 30% of donor) up to 21 days after transplan
tation. The decreases in rates of hepatic P450 monooxygenation were ac
companied by significant increases in microsomal heme oxygenase activi
ty. The data presented in this study suggest the existence of generali
zed stress responses to inflammation that result in tissue- and isozym
e-selective modulation of P450 monooxygenase activity. These responses
most likely reflect complex interactions among multiple inflammatory
mediators as well as perturbations in the levels of endogenous P450 su
bstrates.