{"doi":"10.1093/toxsci/kfae018","title":"Development of a human liver microphysiological coculture system for higher throughput chemical safety assessment","abstract":"Chemicals in the systemic circulation can undergo hepatic xenobiotic metabolism, generate metabolites, and exhibit altered toxicity compared with their parent compounds. This article describes a 2-chamber liver-organ coculture model in a higher-throughput 96-well format for the determination of toxicity on target tissues in the presence of physiologically relevant human liver metabolism. This 2-chamber system is a hydrogel formed within each well consisting of a central well (target tissue) and an outer ring-shaped trough (human liver tissue). The target tissue chamber can be configured to accommodate a three-dimensional (3D) spheroid-shaped microtissue, or a 2-dimensional (2D) cell monolayer. Culture medium and compounds freely diffuse between the 2 chambers. Human-differentiated HepaRG liver cells are used to form the 3D human liver microtissues, which displayed robust protein expression of liver biomarkers (albumin, asialoglycoprotein receptor, Phase I cytochrome P450 [CYP3A4] enzyme, multidrug resistance-associated protein 2 transporter, and glycogen), and exhibited Phase I/II enzyme activities over the course of 17 days. Histological and ultrastructural analyses confirmed that the HepaRG microtissues presented a differentiated hepatocyte phenotype, including abundant mitochondria, endoplasmic reticulum, and bile canaliculi. Liver microtissue zonation characteristics could be easily modulated by maturation in different media supplements. Furthermore, our proof-of-concept study demonstrated the efficacy of this coculture model in evaluating testosterone-mediated androgen receptor responses in the presence of human liver metabolism. This liver-organ coculture system provides a practical, higher-throughput testing platform for metabolism-dependent bioactivity assessment of drugs/chemicals to better recapitulate the biological effects and potential toxicity of human exposures.","journal":"Toxicological Sciences","year":2024,"id":462915,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":7,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9192,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1130802,"name":"Samantha J. Madnick","orcid":"0000-0003-3631-0556","position":1,"is_corresponding":false},{"id":1293239,"name":"Sophia Zheng","orcid":null,"position":2,"is_corresponding":false},{"id":1292736,"name":"Tessa C.A. van Tongeren","orcid":"0000-0002-6068-485X","position":3,"is_corresponding":false},{"id":1292737,"name":"Susan J. Hall","orcid":"0000-0001-6738-5054","position":4,"is_corresponding":false},{"id":490571,"name":"Hui Li","orcid":"0000-0003-4759-1779","position":5,"is_corresponding":false},{"id":1293240,"name":"Suzanne M. Martin","orcid":null,"position":6,"is_corresponding":false},{"id":1292738,"name":"Sandrine Spriggs","orcid":"0000-0002-7252-3658","position":7,"is_corresponding":false},{"id":1252565,"name":"Paul L. Carmichael","orcid":"0000-0003-1353-9032","position":8,"is_corresponding":false},{"id":562066,"name":"Wei Chen","orcid":"0000-0002-6857-7696","position":9,"is_corresponding":false},{"id":238842,"name":"David Ames","orcid":null,"position":10,"is_corresponding":false},{"id":1293241,"name":"Lori A. Breitweiser","orcid":null,"position":11,"is_corresponding":false},{"id":1293242,"name":"Heather E. Pence","orcid":null,"position":12,"is_corresponding":false},{"id":1293243,"name":"Andrew J. Bowling","orcid":null,"position":13,"is_corresponding":false},{"id":353072,"name":"Kamin J. Johnson","orcid":"0000-0003-4550-5566","position":14,"is_corresponding":false},{"id":1292739,"name":"Richard Cubberley","orcid":"0000-0002-5464-0068","position":15,"is_corresponding":false},{"id":720326,"name":"Jeffrey R. Morgan","orcid":"0000-0002-7546-3443","position":16,"is_corresponding":false},{"id":755952,"name":"Kim Boekelheide","orcid":"0000-0003-4564-8057","position":17,"is_corresponding":false},{"id":720324,"name":"Blanche C. Ip","orcid":"0000-0003-0063-5535","position":0,"is_corresponding":true}],"reference_count":70,"raw_metadata":null,"created_at":"2026-07-19T02:04:24.680035Z","pmid":"38335931","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}