The regulatory roles of pparα on hepatic drug-metabolizing enzymes in primary sclerosing cholangitis Syrian hamsters

Abstract

Primary sclerosing cholangitis (PSC) is a chronic liver disease characterized by bile duct inflammation and fibrosis, ultimately leading to liver dysfunction. The role of peroxisome proliferator-activated receptor α (pparα) in regulating hepatic drug-metabolizing enzymes, including cytochrome P450s (P450s) and UDP-glucuronosyltransferases (UGTs), in PSC remains insufficiently understood. In this study, wild-type and pparα −/− Syrian hamsters were used to establish a PSC model, aiming to investigate the effects of pparα on the expression and activity of P450 and UGT enzymes. Sequential windowed acquisition of all theoretical fragment ions profiling and multiple reaction monitoring mass spectrometry with high resolution assays revealed a significant downregulation of CYP2C27 and CYP2D20 in pparα−/− hamsters. Enzymatic kinetic assays demonstrated reduced activity for several enzymes, including CYP1A2 (involved in the metabolism of acetaminophen), CYP2C family (responsible for 4′-hydroxy diclofenac formation), CYP2D family (involved in dextrorphan production), CYP2E1 (involved in 6-hydroxy chlorzoxazone production), and UGTs (responsible for chenodeoxycholic acid 24-acyl-β-D-glucuronide and mycophenolic acid glucuronide formation). These reductions suggest impaired drug metabolism and an increased risk of drug-drug interactions in conditions of reduced pparα function. In contrast, enzymes such as the CYP2B family, CYP3A family, and UGTs involved in N-Acetyl serotonin β-D-glucuronide formation retained their activity, indicating selective pathway preservation in pparα −/− hamsters. These findings highlight the selective regulatory roles of pparα on certain drug-metabolizing enzymes, providing important insights into metabolic regulation in pparα-deficient states.