{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T15:55:08Z","timestamp":1772812508618,"version":"3.50.1"},"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T00:00:00Z","timestamp":1744675200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"<jats:p>Xenoreceptors of the nuclear receptor superfamily, such as pregnane X receptor (PXR), are liver-enriched ligand-activated transcription factors regarded as crucial sensors in xenobiotic exposure and detoxification. PXR controls transcription of many drug-handling genes and influx\/e\ufb04ux transporters, thus playing a crucial role in drug metabolism and excretion. Liver functions have been studied using primary human hepatocytes (PHHs), which, when conventionally cultured, undergo rapid de-differentiation, leaving them unsuitable for long-term studies. Recently, 3D PHHs called spheroids have emerged as an <jats:italic>in vitro<\/jats:italic> model that is similar to <jats:italic>in vivo<\/jats:italic> hepatocytes regarding phenotype and function and represents the first <jats:italic>in vitro<\/jats:italic> model to study the long-term regulation of drug-handling genes by PXR. In this study, we used mathematical modelling to analyze the long-term activation of PXR in 3D PHHs through expression kinetics of three key PXR-regulated drug-metabolizing enzymes, CYP3A4, CYP2C9, and CYP2B6 and the P-glycoprotein e\ufb04ux transporter encoding gene, MDR1. PXR action in 3D PHHs was induced by the antibiotic rifampicin at two clinically relevant concentrations. The results confirmed that high rifampicin concentrations activated PXR nearly to its full capacity. The analysis indicated the highest PXR-induced transcription rate constant for CYP2B6. The rate constant dictating mRNA degradation associated with activated PXR was highest for CYP3A4. Moreover, we measured the metabolic activity of CYP3A4, CYP2C9, and CYP2B6 and quantified their metabolic rate constants. Metabolic activity rate constant of CYP3A4 was found to be the highest whereas that of CYP2B6 was found to be the lowest among the studied enzymes. Our results provide important insight into the regulation of PXR-target genes in 3D PHHs and show that mRNA expression and metabolic activity data can be combined with quantitative analysis to reveal the long-term action of PXR and its effects on drug-handling genes.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012886","type":"journal-article","created":{"date-parts":[[2025,4,15]],"date-time":"2025-04-15T20:07:38Z","timestamp":1744747658000},"page":"e1012886","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["Quantifying expression and metabolic activity of genes regulated by pregnane X receptor in primary human hepatocyte spheroids"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8501-2868","authenticated-orcid":true,"given":"Luk\u00e1\u0161","family":"Lochman","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen Tanaka","family":"Kahiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bechara","family":"Saade","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tom\u00e1\u0161","family":"Smutn\u00fd","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jurjen Duintjer","family":"Tebbens","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Petr","family":"P\u00e1vek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5595-4579","authenticated-orcid":true,"given":"Veronika","family":"Bernhauerov\u00e1","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,4,15]]},"reference":[{"issue":"7","key":"pcbi.1012886.ref001","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1517\/17425255.2012.685237","article-title":"Role of CAR and PXR in xenobiotic sensing and metabolism","volume":"8","author":"YM Wang","year":"2012","journal-title":"Expert Opin Drug Metab Toxicol"},{"issue":"21","key":"pcbi.1012886.ref002","doi-asserted-by":"crossref","first-page":"13801","DOI":"10.1073\/pnas.212494599","article-title":"Regulation of a xenobiotic sulfonation cascade by nuclear pregnane X receptor (PXR)","volume":"99","author":"J Sonoda","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"20","key":"pcbi.1012886.ref003","doi-asserted-by":"crossref","first-page":"3195","DOI":"10.1101\/gad.12.20.3195","article-title":"SXR, a novel steroid and xenobioticsensing nuclear receptor","volume":"12","author":"B Blumberg","year":"1998","journal-title":"Genes Dev"},{"issue":"1","key":"pcbi.1012886.ref004","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/S0092-8674(00)80900-9","article-title":"An orphan nuclear receptor activated by pregnanes defines a novel steroid signaling pathway","volume":"92","author":"SA Kliewer","year":"1998","journal-title":"Cell"},{"issue":"5","key":"pcbi.1012886.ref005","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1172\/JCI3703","article-title":"The human orphan nuclear receptor PXR is activated by compounds that regulate CYP3A4 gene expression and cause drug interactions","volume":"102","author":"JM Lehmann","year":"1998","journal-title":"J Clin Invest"},{"issue":"5525","key":"pcbi.1012886.ref006","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1126\/science.1060762","article-title":"The human nuclear xenobiotic receptor PXR: structural determinants of directed promiscuity","volume":"292","author":"RE Watkins","year":"2001","journal-title":"Science"},{"issue":"1","key":"pcbi.1012886.ref007","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1210\/mend.14.1.0409","article-title":"The pregnane X receptor: a promiscuous xenobiotic receptor that has diverged during evolution","volume":"14","author":"SA Jones","year":"2000","journal-title":"Mol Endocrinol"},{"key":"pcbi.1012886.ref008"},{"key":"pcbi.1012886.ref009"},{"issue":"3","key":"pcbi.1012886.ref010","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1124\/mol.62.3.638","article-title":"Nuclear pregnane X receptor and constitutive androstane receptor regulate overlapping but distinct sets of genes involved in xenobiotic detoxification","volume":"62","author":"JM Maglich","year":"2002","journal-title":"Mol Pharmacol"},{"issue":"3","key":"pcbi.1012886.ref011","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1016\/S0022-3565(24)29202-8","article-title":"Rifampin is a selective, pleiotropic inducer of drug metabolism genes in human hepatocytes: studies with cDNA and oligonucleotide expression arrays","volume":"299","author":"JM Rae","year":"2001","journal-title":"J. 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