The Effects of Uremic Serum from Hemodialysis Patients on Hepatic Cyochrome P450 and VKORC1 Gene Expression in Primary Human Hepatocytes

Warfarin is frequently prescribed to patients with atrial fibrillation (AF) who are on hemodialysis (HD) for stroke prevention regardless of conflicting evidence showing unclear benefits of warfarin, as shown in the systematic review conducted as part of this thesis. We believe an increased variability in INR, correlated with increased adverse events, can be explained by uremic effects on the vitamin K cycle through the downregulation of Cytochrome P450 2C9 (CYP2C9), 4F2 (CYP4F2), and vitamin K epoxide reductase complex subunit 1 (VKORC1) expression. We examined the transcriptional regulation of CYP2C9, CYP4F2 and VKORC1 by human uremic serum, isolated from patients on hemodialysis who are anticoagulated with warfarin for AF, in primary human hepatocytes. We observed no difference in CYP2C9, CYP4F2 and VKORC1 mRNA expression between uremic serum and non-uremic serum treated PHHs. Further studies are warranted to confirm the effects of uremic serum on translational regulation.%%%%M.Sc.