ArticleJournal of pharmacological and toxicological methods
Targeted quantitative proteomic analysis of drug metabolizing enzymes and transporters by nano LC-MS/MS in the sandwich cultured human hepatocyte model.
Article in Journal of pharmacological and toxicological methods. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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28 citing papers in PubMed, 38 citations in OpenAlex.
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- Interindividual variability in imatinib metabolism in human liver microsomes and primary human hepatocytes: Impact of CYP2C8 and CYP3A phenotypes.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Machine Learning Modeling for ABC Transporter Efflux and Inhibition: Data Curation, Model Development, and New Compound Interaction Predictions.Molecular pharmaceutics · 2025Article
- Impact of variation in CYP3A and CYP2C8 on tucatinib metabolic clearance in human liver microsomes.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
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- Estrogen associations with human pregnancy related increases in cytochrome P450 3A activity.Frontiers in pharmacology · 2025Article
- Formation of CYP3A-specific metabolites of ibrutinib in vitro is correlated with hepatic CYP3A activity and 4β-hydroxycholesterol/cholesterol ratio.Clinical and translational science · 2023Article
- Pregnancy related hormones increase CYP3A mediated buprenorphine metabolism in human hepatocytes: a comparison to CYP3A substrates nifedipine and midazolam.Frontiers in pharmacology · 2023Article
- Activity and Expression of Carboxylesterases and Arylacetamide Deacetylase in Human Ocular Tissues.Drug metabolism and disposition: the biological fate of chemicals · 2022Article
- Article
- A novel differentiated HuH-7 cell model to examine bile acid metabolism, transport and cholestatic hepatotoxicity.Scientific reports · 2022Article
- Using Extracellular Vesicles Released by GDNF-Transfected Macrophages for Therapy of Parkinson Disease.Cells · 2022Article
- Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development.Acta pharmaceutica Sinica. B · 2022Review
- Impact of pregnancy related hormones on drug metabolizing enzyme and transport protein concentrations in human hepatocytes.Frontiers in pharmacology · 2022Article
- Extracellular Vesicles as Drug Delivery System for Treatment of Neurodegenerative Disorders: Optimization of the Cell Source.Advanced nanobiomed research · 2021Article
- Negative Regulation of Human Hepatic Constitutive Androstane Receptor by Cholesterol Synthesis Inhibition: Role of Sterol Regulatory Element Binding Proteins.Drug metabolism and disposition: the biological fate of chemicals · 2021Article
- Comparison of Hepatic Transporter Tissue Expression in Rodents and Interspecies Hepatic OCT1 Activity.The AAPS journal · 2021Article
- Carboxylesterase Activities and Protein Expression in Rabbit and Pig Ocular Tissues.Molecular pharmaceutics · 2021Article
- Characterization of primary mouse hepatocyte spheroids as a model system to support investigations of drug-induced liver injury.Toxicology in vitro : an international journal published in association with BIBRA · 2021Article
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
introductionSandwich-cultured human hepatocytes (SCHHs) are the most common in vitro hepatocyte model used for studying hepatic drug disposition and hepatotoxicity. Targeted quantification of key DME and transporter protein expression is useful for in vitro-in vivo extrapolation of drug and xenobiotic clearance and developing corresponding PBPK models. However, established methods for comprehensive quantification of drug metabolizing enzyme (DMEs) and transporter expression in SCHHs are lacking. In this study, a targeted quantitative proteomic isotope dilution nanoLC-MS/MS method developed in our laboratory was adapted to quantify a panel of phase I & II DMEs and transporter proteins in SCHHs under basal and induced conditions.
methodsSCHHs were treated with known inducers of DMEs (Rifampin: PXR activator, CITCO: CAR activator) and transporters (CDCA: FXR activator) or with vehicle control (DMSO) for 72 h. Membrane protein was isolated from the SCHHs using a membrane extraction kit and 30 μg membrane protein was digested with trypsin. The resulting peptides were analyzed by isotope dilution nanoLC-MS/MS to quantify the DMEs and transporters.
resultsUsing the method, we could quantify fourteen phase I and ten phase II DMEs, and twelve uptake/efflux transporters, under basal and induced conditions in the SCHHs. Analysis showed donor to donor variation in basal protein levels of CYP450s, UGTs and transporters, and that basal protein expression of CYP450s and UGTs was higher than that of transporters. In addition, induction of key proteins in response to rifampin, CITCO and CDCA was observed. DISCUSSION: We have successfully quantified protein abundance of multiple phase I and II DMEs and uptake and efflux transporters in SCHHs using a method previously developed in our laboratory. Our method is sufficiently sensitive to quantify inter-donor differences in protein concentrations at the basal level as well as changes in protein expression in response to endogenous and exogenous stimuli.
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