Article
Pharmacology & Pharmacy
Marlies Oorts, Pieter Van Brantegem, Neel Deferm, Sagnik Chatterjee, Erwin Dreesen, Axelle Cooreman, Mathieu Vinken, Lysiane Richert, Pieter Annaert
Summary: Bosentan was evaluated at therapeutically relevant concentrations (2.5-25 μM) in sandwich-cultured human hepatocytes. It altered bile salt disposition and inhibited canalicular secretion of glycochenodeoxycholic acid (GCDCA). Within 24 hours, bosentan caused a shift from canalicular to sinusoidal efflux of GCDCA. These results also indicated reduced GCDCA formation. This study confirmed a direct effect of bosentan on chenodeoxycholic acid conjugation with glycine in liver S9 fraction.
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
(2021)
Article
Toxicology
Hisayoshi Omori, Junko Chikamoto, Megumi Nagahara, Maki Hirata, Takeshige Otoi
Summary: This study investigated the variations in bilirubin metabolic function of canine and human hepatocyte spheroids formed in a 3D culture system. The results showed that the inhibitors atazanavir and ritonavir significantly inhibited the formation of bilirubin glucuronides, especially in human hepatocyte spheroids.
TOXICOLOGY IN VITRO
(2023)
Article
Biochemistry & Molecular Biology
Yung-Te Hou, Chia-Chun Wu, Wen-Ting Wang, Wen-Tse Yang, Ying-Hsiu Liao, Chien-Yu Chen
Summary: In this study, RNA-Seq was used to monitor the maturity and dynamic characteristics of in vitro hepatocyte cultures. The results showed that RNA-Seq can be used to infer the success of in vitro hepatocyte cultures and provide a more comprehensive list of factors related to hepatocyte differentiation. This monitoring system has high potential in medical applications and may also be a novel method for diagnosing liver-related diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Pharmacology & Pharmacy
Taleah Farasyn, Sonia Pahwa, Chao Xu, Wei Yue
Summary: This study demonstrates that pre-incubation with OATP1B inhibitors potentiates inhibitory effects in physiologically relevant primary human hepatocytes, supporting the rationale of the current US FDA draft guidance. IC50 values after inhibitor-preincubation in transporter-expressing cell lines may be used for DDI prediction for the purpose of mitigating false-negative OATP-mediated DDI prediction.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2021)
Article
Toxicology
Christiane Wiemann, Stephanie Melching-Kollmuss, Nina Hambruch, Lucille Wiss, Franz Stauber, Lysiane Richert
Summary: The fungicide boscalid induces thyroid histopathological and hormone effects in rats by inducing liver enzymes. To evaluate the human relevance of liver enzyme induction and its effect on thyroid hormone disruption, an in vitro study was conducted on T4-glucuronidation comparing rat and human hepatocytes. The study found that boscalid induced CYP enzymes and increased T4-glucuronidation in both rat and human hepatocytes, but there were species differences in the induction pattern of UGT genes. Overall, significant increases in T4-glucuronidation were observed in rat hepatocytes but not in human hepatocytes with boscalid exposure.
JOURNAL OF APPLIED TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Congrong Niu, Bill Smith, Yurong Lai
Summary: This study characterized the gene induction by ligands of CAR and AhR in human hepatocytes, showing distinct effects on metabolizing enzyme and drug transporter genes. Different inducers had varying degrees of effects on specific genes, highlighting the importance of assessing transporter gene inductions alongside metabolizing enzyme genes.
FRONTIERS IN PHARMACOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Jiri Vrba, Barbora Papouskova, Katerina Lnenickova, Pavel Kosina, Vladimir Kren, Jitka Ulrichova
Summary: 2,3-Dehydrosilybin A and B are preferentially metabolized through conjugation reactions, with several human UGT and SULT enzymes potentially playing a role in these conjugations.
Article
Chemistry, Multidisciplinary
Sabrina E. Iskandar, Lilly F. Chiou, Tina M. Leisner, Devan J. Shell, Jacqueline L. Norris-Drouin, Cyrus Vaziri, Kenneth H. Pearce, Albert A. Bowers
Summary: This study reports a method to identify covalent cyclic peptide inhibitors in mRNA display. By combining co- and post-translational library diversification strategies, cyclic libraries with reactive dehydroalanines (Dhas) were created and used for selections against two model targets. The most potent hits showed low nanomolar inhibitory activities and disrupted known protein-protein interactions with their selected targets. Overall, this study establishes Dhas as electrophiles for covalent inhibition and demonstrates the synergy of separate library diversification methods in mRNA display for novel applications like covalent inhibitor discovery.
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
(2023)
Article
Chemistry, Multidisciplinary
Ya-li Wu, Ya-ru Xue, Zi-tao Guo, Zhen-dong Chen, Xin-yu Ge, Da-fang Zhong, Xing-xing Diao
Summary: Furmonertinib has been identified as a potent CYP3A4 inducer, comparable to rifampin, making it a potential positive control for evaluating the induction potential of other drug candidates in preclinical studies. Results from the study show that furmonertinib induced CYP3A4 enzyme activity in a manner similar to rifampin in in vitro experiments.
ACTA PHARMACOLOGICA SINICA
(2022)
Article
Toxicology
Andrea Gerdemann, Benedikt Cramer, Gisela H. Degen, Jannik Veerkamp, Georgia Guenther, Wiebke Albrecht, Matthias Behrens, Melanie Esselen, Ahmed Ghallab, Jan G. Hengstler, Hans-Ulrich Humpf
Summary: This study compared the metabolism of AFB(1) in mouse, rat, and human primary hepatocytes, revealing differences in toxification and detoxification mechanisms. Mouse hepatocytes exhibited the fastest metabolism, mainly forming aflatoxin P-1, while human cells produced higher levels of aflatoxin M-1. In addition to glutathione conjugation, phase I metabolism was found to play an important role in AFB(1) detoxification.
ARCHIVES OF TOXICOLOGY
(2023)
Article
Toxicology
Andrea Gerdemann, Benedikt Cramer, Gisela H. Degen, Jannik Veerkamp, Georgia Guenther, Wiebke Albrecht, Matthias Behrens, Melanie Esselen, Ahmed Ghallab, Jan G. Hengstler, Hans-Ulrich Humpf
Summary: This study analyzed the metabolites formed by mouse, rat, and human primary hepatocytes after treatment with different concentrations of Aflatoxin B-1 (AFB(1)). The results showed species-specific differences in the metabolism of AFB(1) and provided insights into the toxification and detoxification mechanisms of AFB(1).
ARCHIVES OF TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Nicholas R. Powell, Harrison Zhao, Joseph Ipe, Yunlong Liu, Todd C. Skaar
Summary: MiRNAs play a crucial role in regulating hepatic genes involved in pharmacokinetics and pharmacodynamics, and genetic variants affecting miRNA binding have been linked to altered drug response. High-throughput methods have been used to directly identify miRNA binding sites and functional mirSNPs in pharmacogenes, providing new insights into the mechanisms underlying miRNA regulation in drug metabolism and response.
CLINICAL PHARMACOLOGY & THERAPEUTICS
(2021)
Review
Immunology
Rula Zain, Mauno Vihinen
Summary: Low-molecular weight chemical compounds have a long history as drugs, but target specificity and binding efficiency remain major obstacles for their clinical relevance. Protein kinases, with their structural similarities and large protein families, present challenges as attractive cellular targets. Bruton tyrosine kinase (BTK), a promising target for B-cell malignancies and autoimmune diseases, has received significant attention. The focus of this review is on the structural properties and binding modes of small-molecule BTK inhibitors, including irreversible and reversible inhibitors.
FRONTIERS IN IMMUNOLOGY
(2021)
Article
Gastroenterology & Hepatology
Jil A. Schrader, Thomas L. Burkard, Yannick Brueggemann, Andre Goemer, Toni L. Meister, Rebecca M. Fu, Ann-Kathrin Mehnert, Viet L. Dao Thi, Patrick Behrendt, David Durantel, Ruth Broering, Florian W. R. Vondran, Daniel Todt, Volker Kinast, Eike Steinmann
Summary: This study identified the EGF receptor (EGFR) as a novel host factor for HEV and revealed the significance of EGFR for the HEV entry process. It was found that EGFR itself and its ligand-binding domain, rather than its signaling function, is responsible for the proviral effect. These findings provide new insights into the life cycle of HEV and identify EGFR as a potential target for future antiviral strategies against HEV.
Article
Chemistry, Physical
Liya Feng, Horacio Perez-Sanchez, Qifeng Bai
Summary: This study investigates the interaction between Smoothened (SMO) and cholesterol using molecular dynamics simulations and Markov state model analysis. The results suggest that covalently bound cholesterol has better stability and configuration transformation pathways compared to noncovalently bound cholesterol at the residue Asp95 position of SMO.
PHYSICAL CHEMISTRY CHEMICAL PHYSICS
(2022)