{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T16:27:00Z","timestamp":1786724820916,"version":"build-2736575974"},"reference-count":69,"publisher":"American Chemical Society (ACS)","issue":"8","license":[{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-029"},{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-037"},{"start":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T00:00:00Z","timestamp":1782086400000},"content-version":"stm-asf","delay-in-days":0,"URL":"https:\/\/doi.org\/10.15223\/policy-045"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["20H03406"],"award-info":[{"award-number":["20H03406"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,14]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cancer cachexia is frequently associated with altered pharmacokinetics and increased chemotherapy toxicity due to the downregulation of cytochrome P450 (CYP) enzymes. However, the molecular mechanisms driving this broad metabolic suppression remain poorly understood. This study investigated whether tumor-derived parathyroid hormone-related protein (PTHrP) is associated with, and may contribute to, suppression of multiple CYP families. In a rat cachexia model, protein expression of CYP3A, CYP1A, CYP2C, CYP2D, and CYP2E1 was significantly downregulated in both the liver and small intestine. Consistent with these changes, pharmacokinetic analyses using a CYP substrate cocktail demonstrated markedly increased AUC and reduced clearance for probe drugs. In vitro experiments showed that PTHrP treatment reduced these CYP isoforms in primary rat hepatocytes. In human data sets, analysis of The Cancer Genome Atlas (TCGA) hepatocellular carcinoma (HCC) data set revealed a significant negative correlation between PTHrP and CYP gene expression, together with enrichment of NF-\u03baB-related transcriptional programs. Furthermore, multimodal analysis using single-cell RNA sequencing and spatial transcriptomics demonstrated that PTHrP-high tumor regions exhibit suppressed xenobiotic metabolism. Additionally, in breast cancer liver metastases, high tumor PTHrP expression correlated with reduced CYP expression in surrounding nontumor hepatocytes, consistent with a possible paracrine relationship. Collectively, these results support an association between tumor-derived PTHrP and suppression of drug-metabolizing programs. They further suggest that PTHrP may be one contributing factor, but not definitive proof of a principal suppressor, and should therefore be considered a candidate biomarker requiring further mechanistic and clinical validation.<\/jats:p>","DOI":"10.1021\/acsptsci.6c00079","type":"journal-article","created":{"date-parts":[[2026,6,22]],"date-time":"2026-06-22T08:42:52Z","timestamp":1782117772000},"page":"2234-2249","source":"Crossref","is-referenced-by-count":0,"title":["Tumor-derived Parathyroid Hormone-Related Protein\nIs Associated with Suppression of Cytochrome P450 Expression: Evidence\nFrom Multimodal Transcriptomics"],"prefix":"10.1021","volume":"9","author":[{"given":"Issei","family":"Fujita","sequence":"first","affiliation":[{"name":"Kumamoto University , , 5-1 Oe-honmachi, Chuo-ku , ,","place":["Kumamoto, Japan, 862-0973"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsubasa","family":"Kaji","sequence":"additional","affiliation":[{"name":"Kumamoto University , , 5-1 Oe-honmachi, Chuo-ku , ,","place":["Kumamoto, Japan, 862-0973"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isamu","family":"Noguchi","sequence":"additional","affiliation":[{"name":"Kumamoto University , , 5-1 Oe-honmachi, Chuo-ku , ,","place":["Kumamoto, Japan, 862-0973"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai","family":"Tokumaru","sequence":"additional","affiliation":[{"name":"Kumamoto University , , 5-1 Oe-honmachi, Chuo-ku , ,","place":["Kumamoto, Japan, 862-0973"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Maeda","sequence":"additional","affiliation":[{"name":"Kyoto Pharmaceutical University , , 5 Nakauchi-cho, Misasagi, Yamashina-ku , ,","place":["Kyoto, Japan, 607-8414"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Maruyama","sequence":"additional","affiliation":[{"name":"Kumamoto University , , 5-1 Oe-honmachi, Chuo-ku , ,","place":["Kumamoto, Japan, 862-0973"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-4102-532X","authenticated-orcid":true,"given":"Hiroshi","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Kumamoto University , , 5-1 Oe-honmachi, Chuo-ku , ,","place":["Kumamoto, Japan, 862-0973"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,6,22]]},"reference":[{"key":"2026081411074987300_cit1","doi-asserted-by":"publisher","first-page":"24","DOI":"10.21037\/apm.2018.08.07","article-title":"Measuring\ncachexia-diagnostic criteria","volume":"8","author":"Dev","year":"2019","journal-title":"Ann. Palliat.\nMed."},{"key":"2026081411074987300_cit2","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1053\/j.jrn.2013.01.001","article-title":"Etiology of the\nprotein-energy wasting syndrome in chronic kidney disease: a consensus\nstatement from the International Society of Renal Nutrition and Metabolism\n(ISRNM)","volume":"23","author":"Carrero","year":"2013","journal-title":"J. Ren. Nutr."},{"key":"2026081411074987300_cit3","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1164\/rccm.201710-2140CI","article-title":"Skeletal Muscle Dysfunction\nin Chronic Obstructive\nPulmonary Disease. What We Know and Can Do for Our Patients","volume":"198","author":"Jaitovich","year":"2018","journal-title":"Am. J. Respir. Crit. Care. Med."},{"key":"2026081411074987300_cit4","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.clnu.2016.07.015","article-title":"ESPEN guidelines\non nutrition in cancer patients","volume":"36","author":"Arends","year":"2017","journal-title":"Clin. Nutr."},{"key":"2026081411074987300_cit5","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2023.103965","article-title":"Overcoming\nbarriers to timely recognition and treatment of cancer cachexia: Sharing\nProgress in Cancer Care Task Force Position Paper and Call to Action","volume":"185","author":"Arends","year":"2023","journal-title":"Crit. Rev. Oncol. Hematol."},{"key":"2026081411074987300_cit6","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1186\/s13045-023-01454-0","article-title":"Cancer cachexia: molecular mechanisms\nand treatment strategies","volume":"16","author":"Setiawan","year":"2023","journal-title":"J. Hematol. Oncol."},{"key":"2026081411074987300_cit7","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1038\/nature13528","article-title":"Tumour-derived\nPTH-related protein\ntriggers adipose tissue browning and cancer cachexia","volume":"513","author":"Kir","year":"2014","journal-title":"Nature"},{"key":"2026081411074987300_cit8","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1016\/j.cmet.2015.11.003","article-title":"PTH\/PTHrP\nReceptor Mediates Cachexia in Models of Kidney Failure and Cancer","volume":"513","author":"Kir","year":"2014","journal-title":"Cell. Metab."},{"key":"2026081411074987300_cit9","doi-asserted-by":"publisher","first-page":"1982","DOI":"10.3390\/cancers15071982","article-title":"Parathyroid\nHormone-Related Protein\/Parathyroid Hormone\nReceptor 1 Signaling in Cancer and Metastasis","volume":"15","author":"Zhao","year":"2023","journal-title":"Cancers (Basel)"},{"key":"2026081411074987300_cit10","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0079603","article-title":"Pharmacokinetics\nof drugs in cachectic patients: a\nsystematic review","volume":"8","author":"Trobec","year":"2013","journal-title":"PLoS One"},{"key":"2026081411074987300_cit11","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1207\/S15327914NC4602_07","article-title":"Baseline nutritional\nassessment in advanced cancer patients receiving palliative chemotherapy","volume":"46","author":"Slaviero","year":"2003","journal-title":"Nutr. Cancer."},{"key":"2026081411074987300_cit12","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1002\/jcph.112","article-title":"Cancer cachexia\nraises the plasma concentration of oxymorphone through the reduction\nof CYP3A but not CYP2D6 in oxycodone-treated patients","volume":"53","author":"Naito","year":"2013","journal-title":"J. Clin. Pharmacol."},{"key":"2026081411074987300_cit13","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1007\/s13318-018-0495-5","article-title":"Reduced Clearance\nof Phenobarbital in Advanced Cancer Patients near the End of Life","volume":"44","author":"Nakayama","year":"2019","journal-title":"Eur. J. Drug. Metab. Pharmacokinet."},{"key":"2026081411074987300_cit14","doi-asserted-by":"publisher","first-page":"1251","DOI":"10.1038\/sj.bjc.6604699","article-title":"CYP2C19 pharmacogenetics\nin advanced cancer: compromised function independent of genotype","volume":"99","author":"Helsby","year":"2008","journal-title":"Br. J. Cancer."},{"key":"2026081411074987300_cit15","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1046\/j.1365-2125.2003.01733.x","article-title":"Polymorphisms in the cytochrome P450\nCYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele\nfrequencies, linkage disequilibrium and influence on caffeine metabolism","volume":"55","author":"Sachse","year":"2003","journal-title":"Br. J. Clin. Pharmacol."},{"key":"2026081411074987300_cit16","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1002\/jcsm.12012","article-title":"Influence of cancer cachexia on drug liver metabolism\nand renal elimination in rats","volume":"6","author":"Cvan Trobec","year":"2015","journal-title":"J. Cachexia.\nSarcopenia. Muscle."},{"key":"2026081411074987300_cit17","doi-asserted-by":"publisher","first-page":"4322","DOI":"10.1021\/acs.molpharmaceut.1c00490","article-title":"Involvement of the Parathyroid Hormone-Related\nProtein on Changes in the CYP3A Expression in Cancer Cachexia","volume":"18","author":"Fujita","year":"2021","journal-title":"Mol. Pharmaceutics"},{"key":"2026081411074987300_cit18","doi-asserted-by":"publisher","first-page":"2280","DOI":"10.1172\/JCI26283","article-title":"Mutual repression\nbetween\nsteroid and xenobiotic receptor and NF-kappaB signaling pathways links\nxenobiotic metabolism and inflammation","volume":"116","author":"Zhou","year":"2006","journal-title":"J. Clin.\nInvest."},{"key":"2026081411074987300_cit19","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.3390\/genes11121509","article-title":"Distinct\nEffects of Inflammation on Cytochrome P450 Regulation and Drug Metabolism:\nLessons from Experimental Models and a Potential Role for Pharmacogenetics","volume":"11","author":"de Jong","year":"2020","journal-title":"Genes (Basel)"},{"key":"2026081411074987300_cit20","doi-asserted-by":"publisher","first-page":"286","DOI":"10.2133\/dmpk.14.286","article-title":"Moment analysis program\navailable on Microsoft Excel","volume":"14","author":"Tabata","year":"1999","journal-title":"Xenobiol. 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Res."},{"key":"2026081411074987300_cit29","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1101\/gr.240663.118","article-title":"Benchmark\nand integration of resources for the estimation of human transcription\nfactor activities","volume":"29","author":"Garcia-Alonso","year":"2019","journal-title":"Genome. Res."},{"key":"2026081411074987300_cit30","doi-asserted-by":"publisher","first-page":"5692","DOI":"10.1038\/s41467-021-25960-2","article-title":"Confronting false discoveries\nin single-cell differential\nexpression","volume":"12","author":"Squair","year":"2021","journal-title":"Nat. Commun."},{"key":"2026081411074987300_cit31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104810","article-title":"A web-based integrative transcriptome\nanalysis, RNAseqChef, uncovers\nthe cell\/tissue type-dependent action of sulforaphane","volume":"299","author":"Etoh","year":"2023","journal-title":"J. Biol. Chem."},{"key":"2026081411074987300_cit32","doi-asserted-by":"publisher","first-page":"4594","DOI":"10.1038\/s41467-022-32283-3","article-title":"A single-cell atlas\nof the multicellular ecosystem of primary and metastatic hepatocellular\ncarcinoma","volume":"13","author":"Lu","year":"2022","journal-title":"Nat. Commun."},{"key":"2026081411074987300_cit33","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s13059-017-1382-0","article-title":"SCANPY: large-scale\nsingle-cell gene\nexpression data analysis","volume":"19","author":"Wolf","year":"2018","journal-title":"Genome. Biol."},{"key":"2026081411074987300_cit34","doi-asserted-by":"publisher","first-page":"D1017","DOI":"10.1093\/nar\/gkaf1117","article-title":"DeepSpaceDB:\na spatial transcriptomics\natlas for interactive in-depth analysis of tissues and tissue microenvironments","author":"Honcharuk","year":"2025","journal-title":"Nucleic. Acids. 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Biol."},{"key":"2026081411074987300_cit38","doi-asserted-by":"publisher","first-page":"420","DOI":"10.1016\/j.yexcr.2003.11.028","article-title":"PTH-related protein\nenhances MCF-7\nbreast cancer cell adhesion, migration, and invasion via an intracrine\npathway","volume":"294","author":"Shen","year":"2004","journal-title":"Exp. Cell. Res."},{"key":"2026081411074987300_cit39","doi-asserted-by":"publisher","first-page":"1394","DOI":"10.1038\/sj.bjc.6603720","article-title":"PTHrP increases transcriptional activity\nof the integrin subunit alpha5","volume":"96","author":"Anderson","year":"2007","journal-title":"Br. J. 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Res."},{"key":"2026081411074987300_cit42","doi-asserted-by":"publisher","first-page":"582","DOI":"10.1002\/hep4.1172","article-title":"Liver-enriched\ntranscription factor expression relates to chronic hepatic failure\nin humans","volume":"2","author":"Guzman-Lepe","year":"2018","journal-title":"Hepatol. Commun."},{"key":"2026081411074987300_cit43","doi-asserted-by":"publisher","first-page":"287","DOI":"10.2133\/dmpk.22.287","article-title":"Role of human\nhepatocyte nuclear factor 4alpha in the\nexpression of drug-metabolizing enzymes and transporters in human\nhepatocytes assessed by use of small interfering RNA","volume":"22","author":"Kamiyama","year":"2007","journal-title":"Drug. Metab. Pharmacokinet."},{"key":"2026081411074987300_cit44","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1038\/nm815","article-title":"The orphan nuclear receptor HNF4alpha\ndetermines PXR- and CAR-mediated xenobiotic induction of CYP3A4","volume":"9","author":"Tirona","year":"2003","journal-title":"Nat. Med."},{"key":"2026081411074987300_cit45","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1042\/BJ20060169","article-title":"Inhibition of hepatocyte nuclear\nfactor 4 transcriptional activity by the nuclear factor kappaB pathway","volume":"398","author":"Nikolaidou-Neokosmidou","year":"2006","journal-title":"Biochem. J."},{"key":"2026081411074987300_cit46","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1038\/s42003-024-06288-1","article-title":"Downregulation of HNF4A\nenables transcriptomic reprogramming during the hepatic acute-phase\nresponse","volume":"7","author":"Ehle","year":"2024","journal-title":"Commun. 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Dispos."},{"key":"2026081411074987300_cit50","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1007\/s00228-016-2116-z","article-title":"Relationships between\noxycodone pharmacokinetics, central symptoms, and serum interleukin-6\nin cachectic cancer patients","volume":"72","author":"Sato","year":"2016","journal-title":"Eur. J. Clin.\nPharmacol."},{"key":"2026081411074987300_cit51","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1007\/s40262-024-01369-0","article-title":"Clinical Pharmacology\nof the Antibody-Drug Conjugate Enfortumab Vedotin in Advanced Urothelial\nCarcinoma and Other Malignant Solid Tumors","volume":"63","author":"Tang","year":"2024","journal-title":"Clin. Pharmacokinet."},{"key":"2026081411074987300_cit52","doi-asserted-by":"publisher","first-page":"3275","DOI":"10.7150\/jca.86746","article-title":"Adverse Event\nProfile Differences between Trastuzumab Emtansine and Trastuzumab\nDeruxtecan: A Real-world, Pharmacovigilance Study","volume":"14","author":"Liu","year":"2023","journal-title":"J. Cancer."},{"key":"2026081411074987300_cit53","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1093\/abt\/tbaf005","article-title":"Fundamental properties and principal areas of focus\nin antibody-drug conjugates formulation development","volume":"8","author":"Wen","year":"2025","journal-title":"Antib. Ther."},{"key":"2026081411074987300_cit54","doi-asserted-by":"publisher","first-page":"3041","DOI":"10.1681\/ASN.2006010035","article-title":"Role of parathyroid hormone in the downregulation of\nliver cytochrome P450 in chronic renal failure","volume":"17","author":"Michaud","year":"2006","journal-title":"J. Am. Soc. 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