12,378 results match your criteria cyp enzymes

Mutagenicity risk prediction of PAH and derivative mixtures by in silico simulations oriented from CYP compound I-mediated metabolic activation.

Sci Total Environ 2021 May 7;787:147596. Epub 2021 May 7.

Key Laboratory of Modern Toxicology of Ministry of Education, Center for Global Health, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; State Key Laboratory of Reproductive Medicine, Institute of Toxicology, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China; School of Nursing, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, PR China. Electronic address:

PAHs and their derivatives are the main sources of mutagenicity and carcinogenicity in airborne particular matter and cause serious public health and environmental problems. Risk assessment is challenging due to the mixed nature and deficiency of toxicity data of most PAHs and their derivatives. Cytochrome P450 enzymes (CYPs) play important roles in PAH-induced carcinogenicity via metabolic activation, and CYP conformations with compound I structures strongly influence metabolic sites and metabolite species. Read More

View Article and Full-Text PDF

Increased systemic exposure of once daily tacrolimus in renal transplant recipients on marine omega-3 fatty acid supplementation.

Transpl Int 2021 May 15. Epub 2021 May 15.

Department of Renal Medicine, Division of Medicine, Akershus University Hospital, Lørenskog, Norway.

High daily doses of marine omega-3 fatty acids (FAs) from fish and seafood may have beneficial cardiovascular effects in renal transplant recipients (RTRs) (1, 2). A recent randomized clinical trial demonstrated that daily supplementation with high-dose marine omega-3 FAs lowered plasma triglyceride and C-reactive protein levels (1). In some parts of the world, high intake of marine omega-3 FAs is recommended for the general population and it is likely that RTRs use omega-3 FA supplements without consulting a transplant physician (2). Read More

View Article and Full-Text PDF

Comparison of gene expression and biotransformation activity of HepaRG cells under static and dynamic culture conditions.

Sci Rep 2021 May 14;11(1):10327. Epub 2021 May 14.

Wageningen Food Safety Research, P.O. Box 230, 6700 AE, Wageningen, The Netherlands.

Flow conditions have been shown to be important in improving longevity and functionality of primary hepatocytes, but the impact of flow on HepaRG cells is largely unknown. We studied the expression of genes encoding CYP enzymes and transporter proteins and CYP1 and CYP3A4 activity during 8 weeks of culture in HepaRG cells cultured under static conditions (conventional 24-/96-well plate culture with common bicarbonate/CO buffering) and under flow conditions in an organ-on-chip (OOC) device. Since the OOC-device is a closed system, bicarbonate/CO buffering was not possible, requiring application of another buffering agent, such as HEPES. Read More

View Article and Full-Text PDF

Sequencing of the Canine Cytochrome P450 CYP2C41 Gene and Genotyping of Its Polymorphic Occurrence in 36 Dog Breeds.

Front Vet Sci 2021 22;8:663175. Epub 2021 Apr 22.

Faculty of Veterinary Medicine, Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Giessen, Germany.

Cytochrome P450 (CYP) drug metabolizing enzymes play an important role in efficient drug metabolism and elimination. Many CYPs are polymorphic and, thereby, drug metabolism can vary between individuals. In the case of canine CYP2C41, gene polymorphism was identified. Read More

View Article and Full-Text PDF

Effect of GLPG1205, a GPR84 Modulator, on CYP2C9, CYP2C19, and CYP1A2 Enzymes: In Vitro and Phase 1 Studies.

Clin Pharmacol Drug Dev 2021 May 6. Epub 2021 May 6.

Galapagos Biotech Ltd, Cambridge, UK.

GLPG1205 is a novel agent being investigated for the treatment of idiopathic pulmonary fibrosis. GLPG1205 may be concomitantly administered with pirfenidone in future clinical development; therefore, the potential for GLPG1205 to interact with enzymes involved in the metabolism of pirfenidone (cytochrome P450 [CYP] 1A2, CYP2C9, 2C19) was evaluated. In vitro experiments indicated weak inhibition of CYP1A2 and moderate but reversible inhibition of CYP2C9 and CYP2C19 by GLPG1205. Read More

View Article and Full-Text PDF

Creation of a new class of radiosensitizers for glioblastoma based on the mibefradil pharmacophore.

Oncotarget 2021 Apr 27;12(9):891-906. Epub 2021 Apr 27.

Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06510-8034, USA.

Glioblastoma (GBM) is the most common primary malignant tumor of the central nervous system with a dismal prognosis. Locoregional failure is common despite high doses of radiation therapy, which has prompted great interest in developing novel strategies to radiosensitize these cancers. Our group previously identified a calcium channel blocker (CCB), mibefradil, as a potential GBM radiosensitizer. Read More

View Article and Full-Text PDF

Identification of functional cytochrome P450 and ferredoxin from Streptomyces sp. EAS-AB2608 by transcriptional analysis and their heterologous expression.

Appl Microbiol Biotechnol 2021 May 4. Epub 2021 May 4.

Technology Research Association for Next-Generation Natural Products Chemistry (N2PC), Aomi, Tokyo, Japan.

Bioconversion using microorganisms and their enzymes is an important tool in many industrial fields. The discovery of useful new microbial enzymes contributes to the development of industries utilizing bioprocesses. Streptomyces sp. Read More

View Article and Full-Text PDF

Recent developments in predicting CYP-Independent metabolism.

Drug Metab Rev 2021 May 4:1-69. Epub 2021 May 4.

Department of Bioengineering and Therapeutic Sciences, Schools of Pharmacy and Medicine, University of California, San Francisco, CA, USA.

As lead optimization efforts have successfully reduced metabolic liabilities due to cytochrome P450 (CYP)- mediated metabolism, there has been an increase in the frequency of involvement of non-CYP enzymes in the metabolism of investigational compounds. Although there have been numerous notable advancements in the characterization of non-CYP enzymes with respect to their localization, reaction mechanisms, species differences and identification of typical substrates, accurate prediction of non-CYP mediated clearance, with a particular emphasis with the difficulties in accounting for any extrahepatic contributions, remains a challenge. The current manuscript comprehensively summarizes the recent advancements in the prediction of drug metabolism and the to extrapolation of clearance for substrates of non-CYP drug metabolizing enzymes. Read More

View Article and Full-Text PDF

In linezolid underexposure, pharmacogenetics matters: The role of CYP3A5.

Biomed Pharmacother 2021 Apr 30;139:111631. Epub 2021 Apr 30.

Unit of Clinical Pharmacology, L. Sacco University Hospital, Milano, Italy. Electronic address:

The exposure to linezolid is characterized by a large inter-individual variability; age, renal dysfunction and body weight explain this variability only to a limited extent and a considerable portion of it remains unexplained; therefore, we decided to investigate the role of individual genetic background focusing in particular on the risk of linezolid underexposure. 191 patients in therapy with linezolid at the standard dose of 600 mg twice daily were considered. Linezolid plasma concentration was determined at the steady state and classified as "below", "within" or "above" reference range. Read More

View Article and Full-Text PDF

Hepatic Cytochrome P450 Abundance and Activity in the Developing and Adult Göttingen Minipig: Pivotal Data for PBPK Modeling.

Front Pharmacol 2021 15;12:665644. Epub 2021 Apr 15.

Comparative Perinatal Development, Department of Veterinary Sciences, Faculty of Pharmaceutical, Biomedical and Veterinary Sciences, University of Antwerp, Wilrijk, Belgium.

The Göttingen Minipig is gaining ground as nonrodent species in safety testing of drugs for pediatric indications. Due to developmental changes in pharmacokinetics and pharmacodynamics, physiologically based pharmacokinetic (PBPK) models are built to better predict drug exposure in children and to aid species selection for nonclinical safety studies. These PBPK models require high quality physiological and ADME data such as protein abundance of drug metabolizing enzymes. Read More

View Article and Full-Text PDF

Human-relevant concentrations of the antifungal drug clotrimazole disrupt maternal and fetal steroid hormone profiles in rats.

Toxicol Appl Pharmacol 2021 Apr 25;422:115554. Epub 2021 Apr 25.

Division of Diet, Disease Prevention and Toxicology, National Food Institute, Technical University of Denmark, Kemitorvet Building 202, Kongens Lyngby DK-2800, Denmark. Electronic address:

Clotrimazole is a non-prescription and broad-spectrum antifungal drug sold under brand names such as Canesten® and Lotrimin®. It is used to treat different types of fungal infections, from oral thrush to athlete's foot and vaginal mycosis. The level of exposure to clotrimazole is uncertain, as the exact usage amongst self-medicating patients is unclear. Read More

View Article and Full-Text PDF

Conversion of five proluciferin esters by human cytochrome P450 enzymes.

Biotechnol J 2021 Apr 28:e2100007. Epub 2021 Apr 28.

School of Pharmaceutical Science and Technology, Health Sciences Platform, Tianjin University, Tianjin, 300072, China.

Background: Probe substrates are an important tool for activity monitoring of human drug metabolizing enzymes such as cytochromes P450 (CYPs).

Brief Methods: In the present study we have tested human CYPs for metabolization of five proluciferin ester substrates which had previously only been known to be hydroxylated by CYP26A1.

Major Results: It was found that these substrates were converted by another 21 human CYPs, which belong to the CYP families 1 to 4, 7, and 26. Read More

View Article and Full-Text PDF

Insights into oral bioavailability enhancement of therapeutic herbal constituents by cytochrome P450 3A inhibition.

Drug Metab Rev 2021 Apr 27:1-17. Epub 2021 Apr 27.

Science and Technology Innovation Center, Guangzhou University of Chinese Medicine, Guangzhou, China.

Herbal plants typically have complex compositions and diverse mechanisms. Among them, bioactive constituents with relatively high exposure are likely to exhibit therapeutic efficacy. On the other hand, their bioavailability may be influenced by the synergistic effects of different bioactive components. Read More

View Article and Full-Text PDF

Scalable production and application of Pichia pastoris whole cell catalysts expressing human cytochrome P450 2C9.

Microb Cell Fact 2021 Apr 26;20(1):90. Epub 2021 Apr 26.

Department of Chemical, Biological and Environmental Engineering, School of Engineering, Universitat Autònoma de Barcelona, 08193, Bellaterra (Cerdanyola del Vallès), Spain.

Background: Currently, the numerous and versatile applications in pharmaceutical and chemical industry make the recombinant production of cytochrome P450 enzymes (CYPs) of great biotechnological interest. Accelerating the drug development process by simple, quick and scalable access of human drug metabolites is key for efficient and targeted drug development in response to new and sometimes unexpected medical challenges and needs. However, due its biochemical complexity, scalable human CYP (hCYP) production and their application in preparative biotransformations was still in its infancy. Read More

View Article and Full-Text PDF

A high-throughput cell-based gaussia luciferase reporter assay for measurement of CYP1A1, CYP2B6, and CYP3A4 induction.

Xenobiotica 2021 May 3:1-12. Epub 2021 May 3.

Institute of Radiation Medicine Academy of Military Medical Sciences, Beijing, China.

The induction of cytochrome P450s can result in reduced drug efficacy and lead to potential drug-drug interactions. The xenoreceptors-aryl hydrocarbon receptor (AhR), constitutive androstane receptor (CAR), and pregnane X receptor (PXR)-play key roles in CYP induction by xenobiotics. In order to be able to rapidly screen for the induction of three enzymes (CYP1A1, CYP2B6, and CYP3A4), we generated a stable AhR-responsive HepG2 cell line, a stable CAR-responsive HepG2 cell line, and a stable PXR-responsive HepG2 cell line. Read More

View Article and Full-Text PDF

A novel epigenetic mechanism unravels hsa-miR-148a-3p-mediated CYP2B6 downregulation in alcoholic hepatitis disease.

Biochem Pharmacol 2021 Apr 23;188:114582. Epub 2021 Apr 23.

Department of Toxicology, School of Public Health, Qingdao University, Qingdao, China. Electronic address:

Cytochrome P450 (CYP) enzymes play critical roles in drug transformation, and the total CYPs are markedly decreased in alcoholic hepatitis (AH), a fatal alcoholic liver disease. miRNAs are endogenous small noncoding RNAs that regulate many essential biological processes. Knowledge concerning miRNA regulation of CYPs in AH disease is limited. Read More

View Article and Full-Text PDF

Evaluation of the drug-drug interaction potential for trazpiroben (TAK-906), a D/D receptor antagonist for gastroparesis, towards cytochrome P450s and transporters.

Xenobiotica 2021 Jun 21;51(6):668-679. Epub 2021 Apr 21.

Global Drug Metabolism and Pharmacokinetics, Takeda Pharmaceuticals International Co, Cambridge, MA, USA.

Trazpiroben (TAK-906), a peripherally selective dopamine D2/D3 receptor antagonist, is being developed for the treatment of patients with gastroparesis. The potential of trazpiroben to act as a perpetrator or a victim for cytochrome P450 (CYP)- or transporter- mediated drug-drug interactions (DDIs) was evaluated following the latest regulatory guidelines.In vitro studies revealed that trazpiroben is metabolised mainly through a non-CYP pathway (56. Read More

View Article and Full-Text PDF

Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

J Med Chem 2021 May 20;64(9):6085-6136. Epub 2021 Apr 20.

Infectious Diseases Research Collaboration, Kampala, Uganda.

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 () suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. Read More

View Article and Full-Text PDF

In vitro toxic synergistic effects of exogenous pollutants-trimethylamine and its metabolites on human respiratory tract cells.

Sci Total Environ 2021 Apr 6;783:146915. Epub 2021 Apr 6.

Guangdong-Hong Kong-Macao Joint Laboratory for Contaminants Exposure and Health, Guangdong Key Laboratory of Environmental Catalysis and Health Risk Control, Institute of Environmental Health and Pollution control, Guangdong University of Technology, Guangzhou 510006, China; Guangzhou Key Laboratory of Environmental Catalysis and Pollution Control, Key Laboratory of City Cluster Environmental Safety and Green Development (Department of Education, China), School of Environmental Science and Engineering, Guangdong University of Technology, Guangzhou 510006, China.

The wide presence of volatile organic amines in atmosphere has been clarified to relate to adverse effects on human respiratory health. However, toxic effects of them on human respiratory tract and their metabiotic mechanism of in vivo transformation have not been elucidated yet. Herein, cell viability and production of reactive oxygen species (ROSs) were first investigated during acute exposure of trimethylamine (TMA) to bronchial epithelial cells (16HBE), along with identification of toxic metabolites and metabolic mechanisms of TMA from headspace atmosphere and cell culture. Read More

View Article and Full-Text PDF

Influence of vitamin D treatment on functional expression of drug disposition pathways in human kidney proximal tubule cells during simulated uremia.

Xenobiotica 2021 Jun 18;51(6):657-667. Epub 2021 Apr 18.

Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado, Aurora, CO, USA.

Effects of cholecalciferol (VitD) and calcitriol (1,25-VitD), on the expression and function of major vitamin D metabolizing enzymes (cytochrome P450 [CYP]2R1, CYP24A1) and select drug transport pathways (P-gp, /OATP4C1) were evaluated in human kidney proximal tubule epithelial cells (hPTECs) under normal and uraemic serum conditions.hPTECs were incubated with 10% normal or uraemic serum for 24 h followed by treatment with 2% ethanol vehicle, or 100 and 240 nM doses of VitD, or 1,25-VitD for 6 days. The effects of treatment on mRNA and protein expression and functional activity of select CYP enzymes and transporters were assessedUnder uraemic serum, treatment with 1,25-VitD resulted in increased mRNA but decreased protein expression of CYP2R1. Read More

View Article and Full-Text PDF

Current insights into the microbial degradation for pyrethroids: strain safety, biochemical pathway, and genetic engineering.

Chemosphere 2021 Apr 10;279:130542. Epub 2021 Apr 10.

College of Food Science, Sichuan Agricultural University, Ya'an, 625014, China. Electronic address:

As a biologically inspired insecticide, pyrethroids (PYRs) exert evident toxic side effects on non-target organisms. PYRs and their general toxic intermediate 3-phenoxybenzoic acid (3-PBA) have shown high detection rates/levels in human beings recently, for which diet was identified as the major exposure route. Microbial mineralization has emerged as a versatile strategy in addressing such escalating concern. Read More

View Article and Full-Text PDF

Investigating the Utility of Humanized PXR-CAR-CYP3A4/7 Mouse Model to Assess CYP3A-Mediated Induction.

Drug Metab Dispos 2021 Apr 16. Epub 2021 Apr 16.

Preclinical Development Sciences, ORIC Pharmaceuticals, United States

Clinical induction liability is assessed with human hepatocytes. However, underpredictions in the magnitude of clinical induction have been reported. Unfortunately, in vivo studies in animals do not provide additional insight due to species differences in drug metabolizing enzymes and their regulatory pathways. Read More

View Article and Full-Text PDF

Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase.

Nat Commun 2021 04 15;12(1):2260. Epub 2021 Apr 15.

Department of Chemistry & Nanoscience Centre, University of Copenhagen, Copenhagen Ø, Denmark.

Metabolic control is mediated by the dynamic assemblies and function of multiple redox enzymes. A key element in these assemblies, the P450 oxidoreductase (POR), donates electrons and selectively activates numerous (>50 in humans and >300 in plants) cytochromes P450 (CYPs) controlling metabolism of drugs, steroids and xenobiotics in humans and natural product biosynthesis in plants. The mechanisms underlying POR-mediated CYP metabolism remain poorly understood and to date no ligand binding has been described to regulate the specificity of POR. Read More

View Article and Full-Text PDF

Cytochrome P450 Enzyme Inhibition and Herb-Drug Interaction Potential of Medicinal Plant Extracts Used for Management of Diabetes in Nigeria.

Eur J Drug Metab Pharmacokinet 2021 May;46(3):437-450

Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, 7 Greenhouse Rd, Kingston, RI, 02881, USA.

Background And Objective: The use of herbal medicines is common in Africa, and patients often use a combination of herbs and drugs. Concurrent herbal and pharmaceuticals treatments can cause adverse effects through herb-drug interactions (HDI). This study evaluated the potential risk of HDI for five medicinal plants, Vernonia amygdalina, Ocimum gratissimum, Moringa oleifera, Azadirachta indica, and Picralima nitida, using in vitro assays. Read More

View Article and Full-Text PDF

Biochemical and phytoremediation of Plantago major L. to protect tomato plants from the contamination of cypermethrin pesticide.

Environ Sci Pollut Res Int 2021 Apr 12. Epub 2021 Apr 12.

Institute of Pesticide Science, College of Plant Protection, Northwest A&F University, Yangling, 712100, Shaanxi, China.

Phytoremediation is an environmentally friendly therapy to minimize soil pollution. Cypermethrin (CYP) is one of the most frequently used pyrethroid insecticides against a variety of pests. We aimed at evaluating the potential of using an economic plant like tomato (Solanum lycopersicum L. Read More

View Article and Full-Text PDF

Comparison of the inhibitory effects of azole antifungals on cytochrome P450 3A4 genetic variants.

Drug Metab Pharmacokinet 2021 Jan 22;38:100384. Epub 2021 Jan 22.

Division of Clinical Pharmacokinetics, Keio University Faculty of Pharmacy, Shibakoen, Minato-ku, Tokyo, 105-8512, Japan. Electronic address:

Cytochrome P450 (CYP) 3A4 is one of the major drug-metabolizing enzymes. Genetic variants of CYP3A4 with altered activity are one of the factors responsible for interindividual differences in drug metabolism. Azole antifungals inhibit CYP3A4 to cause clinically significant drug-drug interactions. Read More

View Article and Full-Text PDF
January 2021

Co-expression of drug metabolizing cytochrome P450 enzymes and estrogen receptor alpha (ESR1) in human liver: racial differences and the regulatory role of ESR1.

Drug Metab Pers Ther 2021 Apr 6. Epub 2021 Apr 6.

Department of Pharmacotherapy and Translational Research, Center for Pharmacogenomics, College of Pharmacy, University of Florida, Gainesville, FL, USA.

Objectives: The function and expression of cytochrome P450 (CYP) drug metabolizing enzymes is highly variable, greatly affecting drug exposure, and therapeutic outcomes. The expression of these enzymes is known to be controlled by many transcription factors (TFs), including ligand-free estrogen receptor alpha (ESR1, in the absence of estrogen). However, the relationship between the expression of ESR1, other TFs, and CYP enzymes in human liver is still unclear. Read More

View Article and Full-Text PDF