Type of Document	Dissertation
Author	Al-Mohizea, Abdullah M
URN	etd-12062002-115904
Title	DRUG METABOLISM AND TRANSPORT DURING REJECTION OF TRANSPLANTED LIVER
Degree	Doctor of Philosophy
Program	Pharmaceutical Sciences
School	School of Pharmacy
Advisory Committee	Advisor Name Title Raman Venkataramanan Committee Chair Gilbert Burckart Committee Member James Perel Committee Member Reginald Frye Committee Member Regis Vollmer Committee Member
Keywords	cytokines transplantation Organ rejection liver transplantation organ transplantation acute rejection microsomes chronic rejection hepatocytes drug metabolism drug transporters
Date of Defense	2002-11-20
Availability	restricted
Abstract Organ transplantation is an accepted therapy for diseases that result in chronic irreversible failure of various organs. During transplantation, the transplanted organ is subjected to two inflammatory processes, alloantigen-independent (ischemia/reperfusion injury) and alloantigen-dependent (rejection), both of which involve release of cytokines. The objectives of this dissertation were to evaluate the effect of acute rejection of liver in rats on hepatic and extra-hepatic drug metabolizing capacity for phase I and II enzymes, to evaluate the effect of chronic rejection of liver in humans on hepatic metabolizing capacity of phase I and II enzymes, to evaluate the effect of acute and chronic rejection of liver on hepatic and extra-hepatic protein and mRNA expression of P-glycoprotein and to evaluate the effect of different cytokines on the constitutive and inducible hepatic CYP3A4 activity and protein expression in human hepatocytes. Alloantigen-independent inflammation and altered blood flow caused a reduction in hepatic mRNA of different phase I and II enzymes. However, this reduction did not significantly alter protein levels of all CYP450 enzymes studied. Occurrence of rejection resulted in further reduction in mRNA, protein levels and activity of all CYP450s studied. Syngeneic and allogeneic transplantation caused reduction in the metabolic capacity of extra-hepatic tissues and increased expression of P-gp in the liver. Chronic rejection of the liver in humans selectively altered the activity and protein expression of different phase I and II enzymes and increased P-gp protein expression. In human hepatocyte cultures, IL-1â, IL-6 and TNF-á decreased the activity and protein expression of both constitutive and induced forms of CYP3A4 enzyme. Pre-exposing or co-exposing the hepatocytes to cytokines reduced the ability of rifampicin to induce CYP3A4. In conclusion, acute and chronic rejection of liver significantly altered the expression and activity of several drug metabolizing enzymes and transporters. The magnitude of these alterations was higher in acute rejection. Acute rejection also caused alterations in the metabolizing ability and transporters expression in renal and pulmonary tissues. Cytokines play a major role in modulating the activity of drug metabolizing enzymes and transporters and may contribute to the large inter-individual variation in the pharmacokinetics of drugs in transplant patients.
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