Successive and Isoform-Specific Remodeling of Hepatic Drug-Metabolizing Enzymes during Metabolic Dysfunction-Associated Steatotic Liver Disease/Metabolic Dysfunction-Associated Steatohepatitis Progression
Abstract
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.
Related
- Macrophage interferon regulatory factor 7 aggravates the progression of metabolic dysfunction-associated steatohepatitis.
- Integrated multi-omics identifies distinct macrophage alterations during progression of metabolic dysfunction-associated steatohepatitis
- Efficacy and safety of GLP-1 receptor agonists in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) : A systematic review and meta-analysis
- Commentary: Wogonoside alleviates metabolic dysfunction-associated steatohepatitis by modulating AMPK and xCT/GPX4 pathways to restrain lipid dysregulation and ferroptosis
- GLP-1 receptor agonists in metabolic dysfunction-associated steatohepatitis: protocol for a systematic review and meta-analysis of randomized controlled trials
BibTeX
@article{ando2026successive,
title = {{Successive and Isoform-Specific Remodeling of Hepatic Drug-Metabolizing Enzymes during Metabolic Dysfunction-Associated Steatotic Liver Disease/Metabolic Dysfunction-Associated Steatohepatitis Progression}},
author = {Yusuke Ando and Takumi Arai and Yuki Tsukui and Chie Watanabe and Mako Okabe and Yuya Egawa and Satoshi Kitaoka},
journal = {Biological and Pharmaceutical Bulletin},
year = {2026},
month = jul,
doi = {10.1248/bpb.b26-00139},
url = {https://www.jstage.jst.go.jp/article/bpb/49/7/49_b26-00139/_article},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - Successive and Isoform-Specific Remodeling of Hepatic Drug-Metabolizing Enzymes during Metabolic Dysfunction-Associated Steatotic Liver Disease/Metabolic Dysfunction-Associated Steatohepatitis Progression
AU - Yusuke Ando
AU - Takumi Arai
AU - Yuki Tsukui
AU - Chie Watanabe
AU - Mako Okabe
AU - Yuya Egawa
AU - Satoshi Kitaoka
PY - 2026
DA - 2026/07/28
JO - Biological and Pharmaceutical Bulletin
DO - 10.1248/bpb.b26-00139
UR - https://www.jstage.jst.go.jp/article/bpb/49/7/49_b26-00139/_article
AB - 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.
SN - 1347-5215
SN - 0918-6158
ER -