Successive and Isoform-Specific Remodeling of Hepatic Drug-Metabolizing Enzymes during Metabolic...

Metabolic dysfunction-associated steatohepatitis (MASH) is frequently accompanied by metabolic comorbidities that require long-term pharmacotherapy. Because the liver plays a central role in drug metabolism, disease-associated alterations in hepatic drug-metabolizing enzyme expression may substantially affect drug disposition and increase the risk of drug-drug interactions. However, comprehensive and systematic analyses of hepatic drug-metabolizing enzyme expression during metabolic dysfunction-associated steatotic liver disease (MASLD)/MASH progression remain limited. In this study, we performed a comprehensive stage-dependent analysis of hepatic drug-metabolizing enzyme expression using a choline-deficient l-amino acid-defined high-fat diet mouse model of MASLD/MASH. Transcript-level expression profiles of 102 CYP, 22 uridine diphosphate glucuronosyltransferase (UGT), and 21 sulfotransferase (SULT) isoforms were analyzed, of which 75 CYPs, 20 UGTs, and 17 SULTs were significantly expressed in the liver during disease progression. MASLD/MASH progression was associated with widespread but isoform-specific alterations in hepatic drug-metabolizing enzyme expression. Several major CYP isoforms, including members of the CYP2C and CYP3A subfamilies, exhibited sustained or transient downregulation, whereas other isoforms exhibited selective induction or no significant change. Similarly, multiple UGT and SULT isoforms exhibited sustained or transient downregulation, while selective induction was observed in specific isoforms such as Sult4a1, indicating that MASLD/MASH progression induces selective remodeling of hepatic drug-metabolizing enzyme expression rather than uniform suppression. This comprehensive expression profiling provides important insights into disease-associated alterations in hepatic drug metabolism and establishes a basis for improved prediction of drug disposition and safer, more individualized pharmacotherapy in patients with MASLD/MASH.