Preliminary report on the effect of xenoperfusion with human blood on cyclosporin A metabolism and cytochrome-P-4503A4-mRNA expression in a pig liver perfusion model

Abstract

Objectives: Little is known about the effect of ischemia/reperfusion with xenogenic blood on function and gene expression of CYP3A4, the enzyme largely responsible for the metabolism of the immunosuppressants Cyclosporin A (CsA) and Tacrolimus. Design and methods: In a pig liver perfusion model, we have compared the effect of perfusion (3 h) after 20 h cold storage, with either pig or human blood on CsA metabolism and CYP3A4-mRNA expression. CYP3A4-mRNA was quantified by RT-PCR, CsA and its major metabolites AM1, AM9, AM4N by RP-HPLC. IL-6 served as inflammation marker, GLDH and ALT to estimate tissue damage. Results: Inflammatory response and tissue damage were more extensive during xenoperfusion. CYP3A4 expression decreased similarly during xenogenic and allogenic perfusion. CsA conversion to its metabolites was also comparable during xeno- and alloperfusion. Conclusion: There is no evidence that during the early reperfusion period pig liver CYP3A4 is severely affected if the organ is xenoperfused with human blood in comparison with alloperfusion. (C) 2001 The Canadian Society of Clinical Chemists. All rights reserved.