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

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. mCYP3A4-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.