Article
Pharmacology & Pharmacy
Tien-Yu Chang, Hong-Jaan Wang, Shu-Hao Hsu, Ming-Ling Chang, Li-Ting Kao, Li-Heng Pao
Summary: This study employed a logistic regression method to differentiate the optimal timing of use between the well-stirred model (WSM) and modified well-stirred model (MWSM) in drug hepatic clearance (CLH) prediction. The results showed that the MWSM, with a new empirical approach, provided a more precise prediction compared to previous methods, highlighting its necessity and potential.
EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES
(2022)
Article
Pharmacology & Pharmacy
David C. Tess, George Chang, Christopher Keefer, Anthony Carlo, Rhys Jones, Li Di
Summary: In vitro-in vivo extrapolation and empirical scaling factors were developed to predict human intrinsic clearance using a large dataset of 455 compounds. Different scaling factors were identified for different clearance classification systems and compound classes. The use of human liver microsomes and hepatocytes in the IVIVE model provided accurate predictions, supporting their continued use in metabolism studies.
Article
Cell Biology
Svetlana Rodimova, Vadim Elagin, Maria Karabut, Irina Koryakina, Alexander Timin, Vladimir Zagainov, Mikhail Zyuzin, Elena Zagaynova, Daria Kuznetsova
Summary: Finding new criteria, testing drugs for hepatotoxicity, and studying the mechanisms of hepatotoxicity at a molecular level are challenging and require adequate research models and tools. Microfluidic chips offer a promising in vitro model, but more complex models are needed for comprehensive information. FLIM is a new label-free approach for studying liver pathology.
Article
Gastroenterology & Hepatology
Macarena Pozo-Morales, Ines Garteizgogeascoa, Camille Perazzolo, Juhoon So, Donghun Shin, Sumeet Pal Singh
Summary: This study successfully observed the changes in hepatocyte calcium dynamics by taking advantage of the transparency of zebrafish larvae. The presence of calcium oscillations, waves, and spikes in vivo were demonstrated, and it was found that calcium waves are related to nutrition intake and negatively regulate starvation-induced lipid droplet accumulation.
Editorial Material
Pharmacology & Pharmacy
Malcolm Rowland, Michael Weiss, K. Sandy Pang
Summary: Clearance concepts play a crucial role in drug development and therapy. The well-stirred model (WSM) is widely used in pharmacokinetics to describe hepatic elimination due to its simplicity. Recently, Kirchhoff's laws of electrical network have been applied to organ clearance, claiming to yield the same equation for hepatic clearance as the WSM. However, this commentary argues that the assumptions made by Kirchhoff's approach are essentially the same as those of the WSM, and raises concerns about the interpretation of permeability or transport parameters.
DRUG METABOLISM AND DISPOSITION
(2023)
Article
Agriculture, Dairy & Animal Science
C. J. Ottemann Abbamonte, T. R. Overton, A. D. Beaulieu, J. K. Drackley
Summary: L-carnitine increased the oxidation and decreased the esterification of palmitate in isolated hepatocytes. Propionate increased palmitate oxidation in phlorizin-treated wethers but decreased it in control wethers. Acetate decreased palmitate esterification in control wethers but had a blunted effect in phlorizin-treated wethers.
JOURNAL OF DAIRY SCIENCE
(2021)
Article
Biology
Ngozi D. Akingbesote, Brooks P. Leitner, Daniel G. Jovin, Reina Desrouleaux, Dennis Owusu, Wanling Zhu, Zongyu Li, Michael N. Pollak, Rachel J. Perry
Summary: This study investigates metabolic scaling from multiple perspectives and finds that it is not only related to oxygen consumption, but also to other metabolic processes. It is regulated at the level of gene and protein expression, enzyme activity, and substrate supply.
Review
Chemistry, Inorganic & Nuclear
Shin A. Yoon, Yujin Cha, Maxine Mambo Fortibui, Song Yi Yoo, Eun-Young Jo, Chulhun Kang, Min Hee Lee
Summary: This tutorial review summarizes recent advances in chemosensors that fluoresce in response to the enzyme systems involved in Phase I xenobiotic metabolism. It discusses both in vitro and in vivo imaging applications on biomedical models, highlighting enzyme systems such as cytochrome P450, monoamine oxidase, nitroreductases, aldehyde dehydrogenases, esterases, and amidases. These enzymatic activities play a role in the metabolism of diverse chemicals and have potential implications in various pathophysiological processes. Enzyme-directed imaging techniques, particularly those utilizing fluorescent chemosensors activated through xenobiotic metabolism, are promising diagnostic modalities with high sensitivity, selectivity, and rapidity in monitoring live biosystems.
COORDINATION CHEMISTRY REVIEWS
(2023)
Article
Agriculture, Dairy & Animal Science
C. J. Ottemann Abbamonte, T. R. Overton, A. D. Beaulieu, J. K. Drackley
Summary: This study investigates the effects of carnitine, epinephrine, and norepinephrine on palmitate oxidation and esterification using hepatocytes from four wethers. Results show that carnitine increases the production of CO2 and acid-soluble products from palmitate, while epinephrine has a quadratic-increasing effect on palmitate oxidation to CO2. Neither epinephrine nor norepinephrine affect the production of acid-soluble products, but both increase the formation of triglyceride from palmitate. Norepinephrine also increases the formation of diglyceride and cholesterol ester from palmitate in the presence of carnitine. Overall, catecholamine treatment has a significant effect on the formation of esterified products from palmitate, with norepinephrine having a more pronounced effect than epinephrine. These findings suggest that conditions leading to catecholamine release may contribute to fat accumulation in the liver.
JOURNAL OF DAIRY SCIENCE
(2023)
Article
Medicine, Research & Experimental
Nenad Manevski, Kenichi Umehara, Neil Parrott
Summary: Hepatocyte intrinsic clearance (CLint) and in vitro-in vivo extrapolation (IVIVE) are used to predict plasma clearance (CLp) in drug discovery, but the specific molecular properties and drug design features that govern these outcomes are poorly understood. This study investigated the success of prospective mouse CLp IVIVE across 2142 chemically diverse compounds and found that predictions were better for smaller, less polar, lipophilic, and neutral compounds with low hydrogen bond donor count. Predictions were also good for compounds resembling central nervous system (CNS) drugs and moderate for classical druglike compounds, but poor for nonclassical compounds. Overall, the current practice of prospective CLp IVIVE is suitable only for CNS-like compounds and well-behaved classical druglike space. The existing methodology will require improvement as drug discovery evolves towards nonclassical and complex chemotypes.
MOLECULAR PHARMACEUTICS
(2023)
Article
Endocrinology & Metabolism
Long Han, Yu Zhang, Shiwei Wan, Qingbo Wei, Wenbing Shang, Guichen Huang, Penghua Fang, Wen Min
Summary: The study revealed that chemerin plays a role in bone metabolism by modulating the differentiation and proliferation of osteoblasts and osteoclasts through Wnt/I3-catenin and RANK signaling pathways. Maintaining a lower level of chemerin may be a strategy for preventing and treating osteoporosis.
MOLECULAR METABOLISM
(2021)
Article
Engineering, Environmental
Meijiao Zhou, Jinhua Li, Mine Du, Jun Wang, Han Yeong Kaw, Lizhong Zhu, Wei Wang
Summary: In this study, it was found that halobenzoquinones (HBQs) can be metabolized by reacting with glutathione (GSH) to form various glutathionylated conjugates (SG-HBQs), and SG-MeO-HBQs were identified as the primary metabolites significantly correlated with the unusual cytotoxicity variation of HBQs. This metabolic pathway can enhance toxicity and provide new insights into the toxicity and metabolic mechanism of HBQs.
ENVIRONMENTAL SCIENCE & TECHNOLOGY
(2023)
Article
Chemistry, Physical
Si Li, Liwei Xu, Meiru Lu, Maozhong Sun, Liguang Xu, Changlong Hao, Xiaoling Wu, Chuanlai Xu, Hua Kuang
Summary: In this study, chiral cobalt oxide nanoparticles stabilized with D- or L-cysteine were found to have no observable cytotoxicity and were internalized by dendritic cells through caveola-dependent endocytosis. The metabolic analysis showed that chiral L-NPs had a similar effect on bile acids in the liver as D-NPs, indicating that low chiroptical activity nanomaterials do not significantly impact metabolism and kinetics under physiological conditions.
Article
Biochemistry & Molecular Biology
Evgeniya Shcherbinina, Tatiana Abakumova, Daniil Bobrovskiy, Ilia Kurochkin, Ksenia Deinichenko, Elena Stekolshchikova, Nickolay Anikanov, Rustam Ziganshin, Pavel Melnikov, Ekaterina Khrameeva, Maria Logacheva, Timofei Zatsepin, Olga Sergeeva
Summary: Long non-coding RNAs play an important role in glucose and lipid metabolism. The murine lncRNA Falcor/LL35, a functional analog of human DEANR1/linc00261, is involved in the regulation of glycolysis and lipid biosynthesis. The depletion of LL35 affects the Notch and NF-kappa B signaling pathways, leading to decreased proliferation and migration of hepatocytes.
Article
Biochemistry & Molecular Biology
Nga-Lai Sou, Yu-Hsuan Huang, Der-Yuan Chen, Yi-Ming Chen, Feng-Yao Tang, Hsin-An Ko, Yi-Hsuan Fan, Yi-Ying Lin, Yi-Cheng Wang, Hui-Ming Chih, Barry Shane, Wen-Nan Huang, En-Pei Isabel Chiang
Summary: MTX specifically depletes mitochondrial 1C supply, which can be ameliorated by folinate supplementation in certain pathways but not in hepatic transmethylation. It is important to carefully address the systematic and tissue-specific formate depletion induced by MTX.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2021)