The effect of selective inhibition of inducible nitric oxide synthase on cytochrome P450 after liver transplantation in a rat model.
BACKGROUND
Activity levels of cytochrome P450 (CYP) provide markers for liver function and graft rejection episodes after orthotopic liver transplantation (OLT). Some in vitro studies have shown decreased CYP activation of inducible nitric oxide synthase (iNOS) in rejecting liver grafts. The aim of this study was to evaluate CYP isoenzyme activity changes in vivo and to examine histopathologic aspects during inhibition of iNOS after treatment with aminoguanidine (AG) using OLT in the rat.


METHODS
Thirty DA-(RT1av1) rats that served as donors and LEWIS-(RT(1)) rats as recipients were divided into three groups: group I (controls, syngeneic rats; n = 6), group II (allogeneic rats without immunosupression; n = 11), and group III (allogeneic rats with AG treatment; n = 13). On postoperative days 5, 8, and 10 we performed laboratory investigations and liver biopsies for histopathologic investigations.


RESULTS
On postoperative day 5, activities of CYP-1A1 and -3A4 were significantly lower (P = .022) in group III and the activity of CYP-1A2 higher (P < .05) compared with group II. At postoperative days 8 and 10, the activities of all CYP isoenzymes were significant higher in AG-treated rats (group III) in contrast with group II after allogeneic OLT without immunosuppression. Histopathologic findings revealed less distinct rejection signs in group III specimens after AG treatment compared with group II.


CONCLUSIONS
Summarizing our results, we concluded that AG treatment led to increased CYP activity and less distinction of graft rejection after OLT in rats.
Department of Surgery, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany. matevossian@chir.med.tu-muenchen.de
E
E
Matevossian
A
A
Novotny
C
C
Knebel
T
T
Brill
M
M
Werner
I
I
Sinicina
M
M
Kriner
M
M
Stangl
S
S
Thorban
N
N
Hüser
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004789:Enzyme Activation; D006146:Guanidines / Q000494:pharmacology; D007700:Kinetics; D016031:Liver Transplantation / Q000502:physiology*; D023421:Models, Animal; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051381:Rats
D015415:Biomarkers; D006146:Guanidines; D003577:Cytochrome P-450 Enzyme System; D052247:Nitric Oxide Synthase Type II; D019363:Cytochrome P-450 CYP1A1; D051544:Cytochrome P-450 CYP3A; C004479:pimagedine