Abstract:
Background: Accurate prediction of metabolic drug-drug interactions (DDIs) is crucial for clinical medication. However, current predominant prediction models are limited. This study was designed to address these limitations by developing a new predictive model that is both accurate and readily applicable.
Methods: A simplified predictive model for metabolic DDIs was developed...
Background: Propranolol is a widely used beta-blocker that exhibits rapid oral absorption, high hepatic extraction, and extensive tissue distribution. Although its absorption and disposition kinetics have been well-documented, interspecies similarities and differences have not been systematically assessed within a unified translational framework. This study aimed to characterize the...
Background: In humans, CYP2A6, the principal enzyme for coumarin and nicotine metabolism, shows wide interindividual genetic variation and environmental regulation, complicating the determination of age- and sex-related differences. African green monkeys, with comparable CYP2A6 activity to humans, were used to investigate age- and sex-effects on CYP2A6 activity.
Methods: Liver and...
Abstract
Background: As a typical prodrug, the clinical application of flurbiprofen axetil is limited by premature hydrolysis mediated by intestinal carboxylesterase 2 (CES2). This premature hydrolysis leads to local accumulation of the active metabolite flurbiprofen in the gastrointestinal tract, causing toxicity, while insufficient systemic exposure results in limited therapeutic efficacy....
Triptolide (TP), the primary bioactive constituent of the traditional Chinese medicine Tripterygium wilfordii, is renowned for its potent pharmacological activities. However, its clinical application is severely restricted by significant hepatotoxicity. Current therapeutic strategies for TP-induced liver injury are limited. In clinical practice, TP is often co-administered with...
Background: In vitro models of human liver development are crucial for studying the impact of xenobiotic exposure on the developing fetus and neonate. However, the limited availability of fetal and neonatal primary human hepatocytes (PHHs) makes it difficult to conduct these studies, leaving these populations vulnerable to empirical drug dosing and possible related toxicities.
Methods:...
The pharmacological modulation of androgens is a cornerstone of managing conditions ranging from hypogonadism to polycystic ovary syndrome (PCOS). However, a major validation gap currently separates the aggressive marketing of commercial supplements from rigorous evidence-based endocrinology. Our analysis critically synthesizes mechanistic and clinical data for multiple natural products to...
Background: Cholestasis is a clinical syndrome of toxic bile acid accumulation due to impaired bile flow, categorized as intrahepatic or extrahepatic, with limited treatment options. Emerging evidence implicates gut microbiota dysregulation in cholestatic liver disease, although its precise mechanistic role remains unclear.
Methods: Intrahepatic and extrahepatic cholestasis models...
Background: Metabolic-dysfunction-associated fatty liver disease (MAFLD) is a chronic liver disorder characterized by disrupted lipid metabolism. The aryl hydrocarbon receptor (AHR), a ligand-dependent transcription factor, is involved in regulating various physiological processes, such as lipid metabolism and immune responses. Recent studies have highlighted the multifaceted regulatory role...
Background: The estrogen axis is regulated through coordinated control of steroid hormone biosynthesis and receptor-mediated transcription. Disruption at either level can alter reproductive, developmental, metabolic, and oncogenic processes.
We developed and applied an integrated approach to identify compounds that target both levels of estrogen regulation: human aromatase (CYP19A1) and...
Submission Type: Poster Presentation
Submitted by: Hae Chan Jeong (Chonnam National University, KR)
Track: New Tools for Studying Drug Metabolism
Biocatalytic synthesis of a novel atorvastatin derivative as an anti-hyperlipidemic drug candidate using sequential reaction of P450 and tyrosinase
Hae Chan Jeong1, Yu-Jin Lee1, Gun Su Cha2, Fikri A. R. Hardiyanti Oktavia1, Chan Mi Park2, Chul-Ho...
Background: Sterol 12α-hydroxylase (CYP8B1) is a promising target for treating metabolic diseases. However, developing selective inhibitors is hindered by incomplete methodologies and the absence of structural guidance. To overcome this, this study adopts an alternative strategy of screening plant-derived triterpenoids and animal bile acids as candidate inhibitors, leveraging their...
Background: Cytochrome P450 11A1 (CYP11A1) is a mitochondrial cytochrome P450 enzyme that catalyzes the conversion of cholesterol to pregnenolone, the first step in steroid hormone biosynthesis, thereby playing a critical role in regulating diverse physiological processes. CYP11A1 requires two redox partners, adrenodoxin reductase (AdR) and adrenodoxin (Adx), to receive electrons from NADPH....
The pregnane X receptor (PXR) is an important regulator of hepatic metabolism, yet mechanistic insights into the effects of pharmacological inhibition using PXR inverse agonists or antagonists on critical genes involved in both xenobiotic and endobiotic metabolism remain limited.
Here, we discovered a novel PXR inverse agonist/antagonist, MI891, which binds to the ligand-binding domain of...
Background: CYP11B1 and CYP11B2 are key enzymes in corticosteroid biosynthesis. The metabolites produced by these enzymes regulate essential physiological processes, including immune function and stress responses. Because the two enzymes share approximately 93% amino acid sequence identity, achieving selective inhibition of one over the other is challenging. Therefore, the objective of this...
Background: Estrogens disrupt bile acid (BA) homeostasis and contribute to the development of intrahepatic cholestasis of pregnancy (ICP). ICP is associated with increased serum BA and bilirubin levels, pruritus, and a higher risk of adverse perinatal outcomes. The constitutive androstane receptor (CAR) plays a key role in regulating genes involved in xenobiotic metabolism and BA...
Abstract:
Background: Human pregnancy relies on tightly controlled maternal estradiol (E2) levels, which are essential to maintain the pregnancy to full term. However, recent studies have indicated hormonal dysregulation of pregnant people receiving antiretroviral therapy, including the non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz. Effectively, efavirenz was...
Background: Cytochrome P450 1A2 (CYP1A2) is a critical isozyme involved in drug metabolism and drug-drug interactions. Developing functional probes that combine high selectivity and suitability for both cell imaging and high-throughput screening (HTS) is crucial for accurately assessing CYP1A2 activity and inhibitor discovery.
Methods: In this study, a series of CYP1A2-specific fluorescent...
Drug-induced liver injury (DILI) is a leading cause of acute liver failure with limited therapeutic options. Cytochrome P450 2E1 (CYP2E1) plays a critical role in DILI pathogenesis by catalyzing the bioactivation of hepatotoxic drugs into reactive intermediates and generating oxidative stress, creating a self-perpetuating injury cycle. However, clinical translation of CYP2E1 inhibitors has...
Background: ALDH1A1 is a key enzyme mediating the metabolic activation of Isosorbide 5-Mononitrate (IS?5?MN). IS-5-MN is frequently co-administered with traditional Chinese medicines (TCMs) in clinical practice. This study aimed to establish an ALDH1A1 activity evaluation system and identify relevant TCM inhibitors for rational co-medication.
Methods: As theophylline acetaldehyde (TA) as a...
Cytochrome P450 2U1 (CYP2U1) is an extrahepatic, lipid-metabolizing membrane enzyme. Due to its high expression in the thymus, this study investigated CYP2U1-mediated biotransformation of two tumor-targeting tyrosine kinase inhibitors, sorafenib and sunitinib, both commonly prescribed for thymus cancers. For comparison, CYP2U1 and CYP2D6 were incorporated into nanodiscs, and their metabolic...
Background: Hepatocellular carcinoma (HCC) is characterized by hypervascularity and profound resistance to current anti-angiogenic therapies. Endothelial metabolic reprogramming is recognized as a critical driver of tumor angiogenesis, yet the key metabolic regulators within tumor endothelial cells (TECs) in HCC remain largely unknown. This study aims to identify these regulators and...
[Background]
Xanthoxylin (2′-hydroxy-4′,6′-dimethoxyacetophenone) is a natural compound found in traditional medicinal plants such as Zanthoxylum species, which have been used for pain relief and inflammatory conditions. While several biological activities have been reported in vitro, the metabolic fate of xanthoxylin in humans remains completely unknown. Understanding its metabolism by human...
Background & Question: Metastasis is the primary cause of death in hepatocellular carcinoma (HCC), a highly metabolic malignancy. Although bile acids are recognized as pleiotropic signaling metabolites, most studies have focused on total bile acid pools and their canonical nuclear receptors, leaving the functional contributions of individual bile acid species largely unexplored....
Abstract
Background: Venetoclax (VEN) shows marked interindividual pharmacokinetic (PK) variability that may affect therapeutic response. As prolonged antibiotic exposure is common in hematologic malignancies and gut microbiota regulates bile acid–mediated solubilization of poorly water-soluble drugs, we investigated whether microbiota disruption alters VEN PK.
Methods: A pseudo-germ-free...
Background: The hepatocellular carcinoma (HCC) microenvironment is characterized by aberrant vasculature, which drives therapeutic resistance and poor prognosis. Vascular normalization strategies can restructure tumor vessels and improve immune infiltration. To date, whether and how a high-fat diet (HFD) modulates tumor vascular function in HCC remains unclear.
Methods: We established...
Abstract
Background:
The induction of cytochrome P450 3A4 (CYP3A4) mediates critical drug-drug interactions and variability in drug response. While ligand-activated PXR drives CYP3A4 transcription, the mechanism enabling efficient transcriptional complex assembly remains unclear. This study investigates whether the long non-coding RNA HNF1A-AS1 regulates this process by promoting...
Background: Increasing research suggests that the gut microbiota serves as a critical metabolic barrier for oral drug absorption. This study aims to investigate whether the commonly used clinical drugs proton pump inhibitors (PPIs) undergo metabolism within the gut microbiota.
Methods: Two representative PPIs, omeprazole (OME) and pantoprazole (PAN), was investigated using an in vitro...
Inhibition of CPT1C ameliorates osteoporosis by regulating αKG levels through interaction with OGDH
Zhong Xiaoyi1, #, Zhu Linlin1, #, Li Julin1, Fang Jian-Hong1, Zhou Yanying1, , Bi Huichang1, *
1 School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China.
Correspondence to: Huichang Bi, bihchang@smu.edu.cn
Background: Osteoporosis is characterized by suppressed...
Background: The analgesic effects of opioids are mediated through four known receptors: mu (MOR), kappa (KOR), delta (DOR), and opioid receptor-like 1 (ORL-1). Of opioid analgesics, mu-opioid agonists (MOAs) are the most commonly used. 2-hydroxytriazolo[4,5-b]pyridine was synthesized as a potential MOA. Pyridines inhibit P-glycoprotein and can reverse multidrug resistance in cancer cells. They...
Context: Genotype-phenotype correlations in congenital adrenal hyperplasia (CAH) are often complicated by rare CYP21A2 missense variants classified as Variants of Uncertain Significance (VUS).
Objective: To resolve the pathogenicity and structural mechanisms of eleven CYP21A2 variants (p.L10del, p.R76K, p.E162G, p.S274Y, p.L308V, p.S373N, p.P387L, p.H393Q, p.R401G, p.R436C, and...
Abstract:
Background: Cytochrome P450 (P450) enzymes are major catalysts involved in the metabolism of drugs, steroids, and fatty acids–hydrophobic molecules that interact with intracellular binding proteins in vivo. A focus is fatty acid binding protein 1 (FABP1), present in liver cytosol at ≥400 µM and reported to bind drugs tightly.
Methods: Purified recombinant human P450s and FABP1 were...
Human cytochrome P450 17A1 (CYP17A1) serves as the gatekeeper of steroidogenesis, partitioning precursors into glucocorticoid or androgen biosynthetic pathways and serving as a critical target for prostate cancer therapy. Despite the availability of static crystal structures, the dynamic pathways by which lipophilic substrates access the buried heme active site from the endoplasmic reticulum...
Abstract
Background: Physiologically based pharmacokinetic (PBPK) models are increasingly used as surrogates for clinical trials in regulatory submissions, yet features distinguishing regulatory-adopted models from academic research remain poorly characterized. This study aimed to identify factors associated with regulatory adoption of PBPK drug-drug interaction (DDI) models through...
Background: Cytochrome P450 17A1 (CYP17A1) is a key steroidogenic enzyme that catalyzes both 17α-hydroxylase and 17,20-lyase reactions, thereby regulating glucocorticoid and sex steroid biosynthesis. Cytochrome b5 (b5) is known to selectively enhance the 17,20-lyase activity of CYP17A1; however, the molecular mechanism underlying this modulation remains incompletely...
Background: Recent advances in lipid nanoparticle delivery (LNP) systems have enabled the development of mRNA vaccines and oligonucleotide therapeutics. Reliable hepatic in vitro systems are essential for the evaluation of metabolism of LNP components and RNA therapeutics.
Methods: The 3D liver spheroid models were constructed using mouse and rat primary hepatocytes as well as HepG2 cell...
The gut microbiota plays a vital role in maintaining human health by contributing to nutrient metabolism, immune function, and the production of bioactive metabolites, and is implicated in inflammatory, metabolic, and neurological disorders, underscoring its important influence on human physiology. Beyond these roles, the gut microbiota is increasingly recognized as an important factor...
UDP-glucuronosyltransferases (UGTs) and cytochromes P450 (P450s, CYPs) are a family of enzymes that catalyze glucuronidation and oxidation. Although these are membrane proteins bound to the endoplasmic reticulum, their topologies are distinct. Therefore, these proteins are considered to function independently. Cumulative evidence suggests that protein¬¬–protein interactions exist between P450...
Our group at the University of Washington focuses on the development of microphysiological models as an alternative to animal testing. I will present case studies on the application of these new approach methodologies (NAMs) in modeling ADME disposition and toxicity of drugs, endobiotics and xenobiotics. These studies are based on the “holy trinity” of ADME NAMs-the intestine, liver and...
Supplemental oxygen administration is frequently encountered in infants and adults with pulmonary insufficiency. Hyperoxia contributes to acute respiratory distress syndrome (ARDS) in humans. In this investigation, we tested the hypotheses that (i) hyperoxia induces CYP1A1 via the formation of 6-Formylindolo[3,2-b]carbazole (FICZ), an endogenous ligand for the Ah receptor (AHR; and (ii) FICZ...
Background: Pirin, a non-heme metalloprotein that occurs widely in human tissues, typically functions as nuclear transcription regulators involved in cancer metastasis. We first revealed that Pirin homologs have the activity of "flavonolase" (quercetinase-like), i.e. catalyzing the oxidative decomposition of plant flavonols with the release of carbon monoxide (CO). (Guo et al.: *ACS...
Abstract:
Background: This study used capecitabine (CAP) as a model prodrug to investigate localized accumulation of active metabolite 5-fluorouracil (5-FU) caused by premature gastrointestinal activation mediated by carboxylesterase (CES). It explored oleanolic acid (OA), a natural CES inhibitor, to delay metabolic activation of CAP in non-target organs, aiming to improve heterogeneous...
Abstract
Background and Aims:
Metabolic dysfunction-associated steatotic liver disease (MASLD) has progressed as the most prevalent chronic liver disease globally, affecting over one-third of the world’s population. The perilipin (Plin) family proteins play a crucial role of hepatic lipid droplets (LDs) accumulation in MASLD. This study demonstrates that Paeonol serves as a potential...
Authors:
Longjie Li (1)†, Mengfan Ye (2) (3)†, Wenhang Xu (1), Xinyan Zhu (1), Haiping Xu (1), Qingfeng He (1), Xiao Zhu (1), Juan Xie (2) (3), Xiaoqiang Xiang (1)
Affiliations:
(1) Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmaceutical Sciences, Fudan University, Shanghai, China
(2) Department of General Medicine at Shanghai Fifth People's Hospital,...
Background: 5F-CUMYL-PeGACLONE (5F-CP) is a novel synthetic cannabinoid containing a 5-fluoropentyl side chain and previous studies have suggested that its toxic effects are not restricted to the nervous system. Synthetic cannabinoids primarily act via the cannabinoid receptor type 1 (CB1) pathway; CB1 activation is generally associated with increased hepatic lipid production. However,...
Background: MG1113 is a humanized immunoglobulin G4 antibody targeting tissue factor pathway inhibitor (TFPI), currently under clinical development for hemophilia. This study aimed to refine a previously developed TMDD model for MG1113 by incorporating both soluble and membrane-bound TFPI (sTFPI-α and mTFPI) along with a transit compartment. Furthermore, we investigated the impact of...
Background: Sepsis remains a major global health challenge, with limited effective therapies targeting dysregulated host responses. Patient heterogeneity represents a critical barrier to treatment optimization. Currently, XueBiJing injection is the only effective agent shown to modulate dysregulated host responses. This study aimed to characterize the pharmacokinetics of XueBiJing in...
Furanoterpenoid diosbulbin B (DSB) is a major component responsible for the hepatotoxicity of herbal medicine Dioscorea bulbifera L. (DBL). The metabolic oxidation of the furan moiety of DSB is considered to initiate its liver toxicity. The resulting reactive intermediate reacts with hepatic protein to form protein covalent binding. DSB-derived protein adduction-based biomarker was...
Background: Rituximab (RTX) is widely used off-label for pediatric patients with frequently relapsing or steroid-dependent nephrotic syndrome (FRNS/SDNS), yet dosing remains extrapolated from B-cell lymphoma regimens. This study characterizes population pharmacokinetics and exposure-response to inform optimal pediatric dosing.
Methods: Thirty-one pediatric patients with FRNS/SDNS were...
Background: The hexapeptide WKYMVm (Wm), a potent agonist of the formyl peptide receptor 2, has shown therapeutic potential in various disease models (e.g., sepsis, lung injury, and cancer). Given that peptide-based drug candidates are often limited by rapid enzymatic degradation and poor membrane permeability, this study investigated the metabolic pathways and oral dosing feasibility of...
Context: 17α-hydroxylase/17,20-lyase deficiency (17-OHD) is a rare form of congenital adrenal hyperplasia characterized by hypertension, hypokalemia, and sexual infantilism. Its spectrum ranges from complete deficiency to partial forms with spontaneous puberty and fertility, yet the molecular basis of this heterogeneity remains unclear.
Objective: To elucidate the pathophysiology of...
Background: Hepatic ischemia‑reperfusion injury (HIRI) remains a major challenge in liver surgery. The pregnane X receptor (PXR) is a key regulator of xenobiotic metabolism and cellular stress responses, yet its role in HIRI is poorly defined. Here, we investigated the function of PXR in both vivo and in vitro models of liver IRI.
Methods: To investigate the role of PXR in hepatic I/R injury,...
Background: Escitalopram (S-CIT) is widely prescribed for depression and anxiety in older adults. A previous study indicated that the impact of CYP2C19 phenotypes on S-CIT pharmacokinetics is more pronounced in older adults than in younger individuals (Jang et al., Clin Pharmacol Ther 2025). This study quantified the risk of drug-drug interactions (DDIs) involving S-CIT in older and...
Abstract:
Background: The formation and accumulation of payload-related catabolites from antibody–drug conjugates (ADCs) in targeted and normal tissues are directly associated with ADC's efficacy and systemic toxicity. Rapid and comprehensive identification of these catabolites in vitro is important for supporting the payload/linker design and facilitating preclinical evaluation of ADCs....
Castration-resistant prostate cancer (CRPC) remains largely driven by persistent androgen receptor (AR) signalling, making CYP17A1 inhibition a validated therapeutic strategy. However, first-generation inhibitors such as abiraterone lack enzymatic selectivity, suppressing both 17α-hydroxylase and 17,20-lyase activities and leading to off-target endocrine disturbances. Seviterenol (VT-464) is a...
Background: Sleep deprivation (SD) impairs diverse physiological functions and contributes to multi-system disorders, emerging as a prevalent public health concern. It has been demonstrated that SD disrupts metabolic homeostasis and drives liver disease progression, from non-alcoholic fatty liver disease to hepatocellular carcinoma. However, the consequences of SD on hepatic cytochrome P450...
Kaige Li1,2,3, Jibira Yakubu1,2,3, Flemming Steen Jørgensen4 , Amit V. Pandey1,2,*
1Pediatric Endocrinology, Diabetology and Metabolism, University Children’s Hospital, Inselspital, Bern, Switzerland.
2Translational Hormone Research Program, Department of Biomedical Research, Faculty of Medicine, University of Bern, Bern, Switzerland.
3Graduate School for Cellular and Biomedical...
Background: CYP3A4 and 3A7 specifically catalyze the tertiary oxidation of deoxychoate (DCA) and glycodeoxycholate (GDCA). The oxidation rates fit well with Hill kinetic model at low substrate concentrations (DCA 1-400 μM, GDCA 30-250 μM), but gradually decrease as substrate levels increase, eventually leading to complete enzyme deactivation above the critical micelle concentration (CMC)....
Double limitation characterizes the use of nuclear receptor (NR) modulation in cancer pharmacotherapy. First, it is approved in only few cancer entities. Second, it is restricted to a small number of NRs. In this study, we aimed to reveal the full potential of NRs as drug targets in anti-cancer therapy by combining bioinformatics, molecular biology and biochemical approaches.
Genome-wide gene...
Background: The synthesis of human drug metabolites (HDMs) is one of the fundamental aspects in pharmacokinetic and pharmacodynamic safety studies, as the U.S. Food and Drug Administration (FDA) requires evaluation of metabolites formed exceeding 10% systemic exposure of the parent drug. Conventional chemical synthesis of HDMs is often limited by low yields and complex procedures, highlighting...
Background: Drug metabolism studies play a critical role in drug development by enabling the prediction of pharmacokinetics and potential drug–drug interactions. Conventional cytochrome P450 enzymes are commonly used for these studies. Unspecific peroxygenases (UPOs), heme-thiolate enzymes structurally related to P450s, have recently emerged as promising alternatives. Unlike P450s, UPOs...
Background: Valine‑tRNA synthetase (VARS), a key member of aminoacyl‑tRNA synthetases, catalyzes valine‑tRNA formation and maintains translational fidelity. Our preliminary TCGA analysis demonstrated that VARS is significantly upregulated in hepatocellular carcinoma (HCC) tissues, and high VARS expression correlates with poorer overall and disease‑free survival, suggesting VARS functions...
