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Tacrolimus is a immunosuppressant drug in transplantation with a narrow therapeutic range and high pharmacokinetic variability. Clinical studies have revealed that  POR*28  contributes enhanced tacrolimus clearance in CYP3A5 expressers. However, it remains unknown that how exactly the  POR  polymorphism could influence the metabolism of tacrolimus via CYP3A5  in vitro . A503V is an amino acid sequence variant encoded by  POR*28 . Wild-type (WT) and A503V POR, with WT CYP3A5 were expressed in recombinant HepG2 cells and reconstituted proteins. Michaelis constant ( Km ) and maximum velocity ( Vmax ) of CYP3A5 with tacrolimus as substrates were determined, and catalytic efficiency is expressed as  Vmax / Km . Both WT and A503V POR down-regulated the CYP3A5 mRNA expression, and WT POR rather than A503V down-regulated the protein expression of CYP3A5 in recombinant HepG2 cells. Compared with WT POR, A503V increased metabolism of tacrolimus by CYP3A5 in both cellular and protein levels. A503V can affect CYP3A5-catalyzed tacrolimus metabolism  in vitro , which suggests that A503V has the potential to serve as a biomarker for tacrolimus treatment in transplantation recipients.

Cytochrome P450 oxidoreductase variant A503V contributes to the increased CYP3A5 activity with tacrolimus in vitro