{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:13:08Z","timestamp":1788221588064,"version":"build-2803163510"},"reference-count":59,"publisher":"American Chemical Society (ACS)","issue":"33","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/L017253\/1"],"award-info":[{"award-number":["BB\/L017253\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/M011208\/1"],"award-info":[{"award-number":["BB\/M011208\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/na","name":"Cypex Ltd","doi-asserted-by":"publisher","award":["BB\/L017253\/1"],"award-info":[{"award-number":["BB\/L017253\/1"]}],"id":[{"id":"10.13039\/na","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,8,25]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>P450 BM3 is a natural fusion protein with a P450 domain fused to its necessary redox partner and capable of binding a range of fatty acids at high catalytic rates. The flexibility of the active site and catalytic efficiency have led to extensive research aimed at modifying substrate and product profiles for its utilization as a biocatalyst. The introduction of a double mutation (DM) at the base of the active site (A82F\/F87V) allows the binding of a broad range of structurally diverse small molecules, including pharmaceutical drugs. Herein, we describe screening with an FDA-approved drug compound library, and the results exhibit the promiscuous nature of the DM BM3 variant. Of the 978 compounds screened; 59% of the library elicited UV\u2013vis spectral shifts indicative of binding with a range of structurally diverse drugs. The interaction of the DM BM3 variant with a range of structurally diverse drugs, with a particular focus on the antidiabetic glitazone (thiazolidinedione) class, was investigated to observe ligand binding modes and metabolite production. BM3-derived metabolites were successfully produced and structurally elucidated for several structurally diverse drugs in the steroid, glitazone, meglitinide, terpene lactone, retinoid, and fibrate classes. The range of modifications performed includes some that are human P450-derived metabolites. Structural elucidation of the troglitazone-bound DM variant P450 domain shows an unusually close crystallographic interaction between the substrate and heme cofactor. We report here the use of the DM BM3 variant as a model for the main human metabolizing P450 enzymes CYP1A1, CYP2B6, CYP2C8, CYP2C9, and CYP3A4, as well as a biotechnological tool for the production of metabolites with diverse functionality.<\/jats:p>","DOI":"10.1021\/acsomega.6c01534","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T01:01:51Z","timestamp":1786582911000},"page":"49151-49162","source":"Crossref","is-referenced-by-count":0,"title":["Expanding the Biocatalytic\nToolbox: A Singular P450\nEnzyme Efficiently Produces Diverse Pharmaceutical Metabolites"],"prefix":"10.1021","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0607-6116","authenticated-orcid":true,"given":"Laura N.","family":"Jeffreys","sequence":"first","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sian","family":"Thistlethwaite","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Cliff","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harshwardhan","family":"Poddar","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahara","family":"Bhanot","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard B.","family":"Tunnicliffe","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Golovanova","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-047X","authenticated-orcid":true,"given":"Katherine","family":"Hollywood","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin W.","family":"Levy","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Voice","sequence":"additional","affiliation":[{"name":"Cypex Ltd ., 6 Tom McDonald Avenue , ,","place":["Dundee, U.K., DD2 1NH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4845-8443","authenticated-orcid":true,"given":"David","family":"Leys","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7193-5044","authenticated-orcid":true,"given":"Kirsty J.","family":"McLean","sequence":"additional","affiliation":[{"name":"University of Huddersfield , , Queensgate , ,","place":["Huddersfield, U.K., HD1 3DH"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan P.","family":"Waltho","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]},{"name":"University of Sheffield , , Firth Court, Western Bank , ,","place":["Sheffield, U.K., S10 2TN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4642-180X","authenticated-orcid":true,"given":"Andrew W.","family":"Munro","sequence":"additional","affiliation":[{"name":"University of Manchester , , ,","place":["Manchester, U.K., M1 7DN"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2299-8644","authenticated-orcid":true,"given":"Hazel M.","family":"Girvan","sequence":"additional","affiliation":[{"name":"University of Huddersfield , , Queensgate , ,","place":["Huddersfield, U.K., HD1 3DH"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"2026083119150848700_cit1","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/128_2010_79","article-title":"Total (Bio)Synthesis:\nStrategies of Nature and of Chemists","volume":"297","author":"Roberts","year":"2010","journal-title":"Top. Current\nChem."},{"issue":"21","key":"2026083119150848700_cit2","doi-asserted-by":"publisher","first-page":"11380","DOI":"10.3390\/ijms222111380","article-title":"A Promiscuous Bacterial P450: The Unparalleled Diversity of BM3 in\nPharmaceutical Metabolism","volume":"22","author":"Thistlethwaite","year":"2021","journal-title":"Int. J. Mol. Sci."},{"issue":"1","key":"2026083119150848700_cit3","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3109\/10408449209145319","article-title":"The Human Hepatic\nCytochromes P450 Involved in Drug\nMetabolism","volume":"22","author":"Wrighton","year":"1992","journal-title":"Crit. Rev. Toxicol."},{"issue":"6","key":"2026083119150848700_cit4","doi-asserted-by":"publisher","first-page":"1880","DOI":"10.1016\/S0021-9258(19)42868-8","article-title":"(Omega-2) Hydroxylation\nof Fatty Acids by a Soluble\nSystem from Bacillus Megaterium","volume":"249","author":"Miura","year":"1974","journal-title":"J. Biol. Chem."},{"issue":"3","key":"2026083119150848700_cit5","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1016\/0005-2760(75)90089-2","article-title":"\u03c9-1, \u03c9-2 and \u03c9-3 Hydroxylation of\nLong-Chain Fatty Acids, Amides and Alcohols by a Soluble Enzyme System\nfrom Bacillus Megatyerium","volume":"388","author":"Miura","year":"1975","journal-title":"Biochimica et Biophysica\nActa (BBA)\/Lipids and Lipid Metabolism"},{"issue":"2","key":"2026083119150848700_cit6","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/S0006-291X(75)80198-7","article-title":"Carbon Monoxide\nand Hydroxymercuribenzoate Sensitivity\nof a Fatty Acid (Omega-2) Hydroxylase from Bacillus Megaterium","volume":"65","author":"Hare","year":"1975","journal-title":"Biochem. Biophys. Res. Commun."},{"issue":"16","key":"2026083119150848700_cit7","doi-asserted-by":"publisher","first-page":"7160","DOI":"10.1016\/S0021-9258(17)38369-2","article-title":"Characterization\nof a Catalytically Self-Sufficient\n119,000-Dalton Cytochrome P-450 Monooxygenase","volume":"261","author":"Narhi","year":"1986","journal-title":"J. Biol. Chem."},{"issue":"14","key":"2026083119150848700_cit8","doi-asserted-by":"publisher","first-page":"6683","DOI":"10.1016\/S0021-9258(18)48296-8","article-title":"Identification and\nCharacterization of Two Functional\nDomains in Cytochrome P-450BM-3, a Catalytically Self-Sufficient Monooxygenase\nInduced by Barbiturates in Bacillus Megaterium","volume":"262","author":"Narhi","year":"1987","journal-title":"J. Biol. Chem."},{"issue":"45","key":"2026083119150848700_cit9","doi-asserted-by":"publisher","first-page":"13421","DOI":"10.1021\/bi010716m","article-title":"Phenylalanine 393\nExerts Thermodynamic Control over\nthe Heme of Flavocytochrome P450 BM3\u2020","volume":"40","author":"Ost","year":"2001","journal-title":"Biochemistry"},{"issue":"2","key":"2026083119150848700_cit10","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/0005-2760(76)90145-4","article-title":"Involvement of a Single Hydroxylase Species in the\nHydroxylation of Palmitate at the \u03c9\u25001, \u03c9\u25002\nand \u03c9\u25003 Positions by a Preparation from Bacillus Megaterium","volume":"431","author":"Ho","year":"1976","journal-title":"Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism"},{"issue":"8","key":"2026083119150848700_cit11","doi-asserted-by":"publisher","first-page":"5560","DOI":"10.1021\/ACSCATAL.4C00086\/SUPPL_FILE\/CS4C00086_SI_002.MP4","article-title":"Choose\nYour Own Adventure: A Comprehensive Database of Reactions Catalyzed\nby Cytochrome P450 BM3 Variants","volume":"14","author":"Fansher","year":"2024","journal-title":"ACS Catal."},{"issue":"45","key":"2026083119150848700_cit12","doi-asserted-by":"publisher","first-page":"18695","DOI":"10.1021\/ja3073462","article-title":"Controlled\nOxidation of Remote Sp 3 C\u2013H Bonds in Artemisinin via P450\nCatalysts with Fine-Tuned Regio-and Stereoselectivity","volume":"134","author":"Zhang","year":"2012","journal-title":"J. Am. Chem. Soc."},{"issue":"1","key":"2026083119150848700_cit13","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1039\/b413068e","article-title":"Biotransformation\nof the Sesquiterpene (+)-Valencene","volume":"3","author":"Sowden","year":"2005","journal-title":"Org. Biomol.\nChem."},{"issue":"30","key":"2026083119150848700_cit14","doi-asserted-by":"publisher","first-page":"12499","DOI":"10.1002\/anie.202003139","article-title":"Regio- and Stereoselective\nSteroid Hydroxylation at C7 by Cytochrome P450 Monooxygenase Mutants","volume":"59","author":"Li","year":"2020","journal-title":"Angew. Chem., Int. Ed."},{"issue":"21","key":"2026083119150848700_cit15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262110728","article-title":"Steroid Hydroxylation\nby Mutant Cytochrome P450 BM3-LG23 Using Two Expression Chassis","volume":"26","author":"Poshekhontseva","year":"2025","journal-title":"Int. J. Mol. Sci."},{"key":"2026083119150848700_cit16","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1021\/acscatal.5c08382","article-title":"Computational\nRedesign and Mechanistic Insights into P450BM3 Enable Regioselective\nC\u2013H Hydroxylation of Structurally Diverse Steroids","volume":"16","author":"Ye","year":"2026","journal-title":"ACS Catal."},{"issue":"4","key":"2026083119150848700_cit17","doi-asserted-by":"publisher","first-page":"3395","DOI":"10.1021\/acscatal.8b00389","article-title":"P450-Catalyzed\nRegio- and Diastereoselective Steroid Hydroxylation: Efficient Directed\nEvolution Enabled by Mutability Landscaping","volume":"8","author":"Acevedo-Rocha","year":"2018","journal-title":"ACS Catal."},{"key":"2026083119150848700_cit200","doi-asserted-by":"publisher","first-page":"1209","DOI":"10.1021\/acs.accounts.0c00591","article-title":"Navigating the Unnatural Reaction\nSpace: Directed Evolution of Heme Proteins for Selective Carbene and\nNitrene Transfer","volume":"54","author":"Yang","year":"2021","journal-title":"Acc. Chem. Res."},{"issue":"1","key":"2026083119150848700_cit18","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-025-61773-3","article-title":"Regulating the N-Oxidation Selectivity\nof P450BM3Monooxygenases for\nN-Heterocycles through Computer-Assisted Structure-Guided Design","volume":"16","author":"Yang","year":"2025","journal-title":"Nat. Commun."},{"issue":"4","key":"2026083119150848700_cit19","doi-asserted-by":"publisher","first-page":"814","DOI":"10.1021\/acs.oprd.5b00282","article-title":"Selective\nand Sustainable P450 Oxygenation\nTechnology","volume":"20","author":"Kaluzna","year":"2016","journal-title":"Org. Process Res. Dev."},{"issue":"43","key":"2026083119150848700_cit20","doi-asserted-by":"publisher","first-page":"11723","DOI":"10.1002\/chem.200900643","article-title":"A Panel of Cytochrome\nP450 BM3 Variants to Produce\nDrug Metabolites and Diversify Lead Compounds","volume":"15","author":"Sawayama","year":"2009","journal-title":"Chem.\u2500A Euro. J."},{"issue":"22","key":"2026083119150848700_cit21","doi-asserted-by":"publisher","first-page":"7595","DOI":"10.1074\/jbc.RA119.011630","article-title":"Characterization of the Structure\nand Interactions of P450 BM3 Using Hybrid Mass Spectrometry Approaches","volume":"295","author":"Jeffreys","year":"2020","journal-title":"J. Biol. Chem."},{"issue":"35","key":"2026083119150848700_cit22","doi-asserted-by":"publisher","first-page":"25387","DOI":"10.1074\/jbc.M113.479717","article-title":"Key Mutations Alter\nthe Cytochrome P450 BM3 Conformational\nLandscape and Remove Inherent Substrate Bias","volume":"288","author":"Butler","year":"2013","journal-title":"J. Biol. Chem."},{"issue":"2","key":"2026083119150848700_cit23","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1042\/BJ20140030","article-title":"Human P450-like\nOxidation of Diverse Proton Pump Inhibitor\nDrugs by \u2018Gatekeeper\u2019 Mutants of Flavocytochrome P450\nBM3","volume":"460","author":"Butler","year":"2014","journal-title":"Biochem. J."},{"issue":"1","key":"2026083119150848700_cit24","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-37330-y","article-title":"Novel Insights\ninto P450 BM3 Interactions with FDA-Approved Antifungal Azole Drugs","volume":"9","author":"Jeffreys","year":"2019","journal-title":"Sci. Rep."},{"key":"2026083119150848700_cit25","doi-asserted-by":"publisher","first-page":"50","DOI":"10.1016\/j.jinorgbio.2012.05.012","article-title":"A Series of\nHybrid\nP450 BM3 Enzymes with Different Catalytic Activity in the Light-Initiated\nHydroxylation of Lauric Acid","volume":"115","author":"Tran","year":"2012","journal-title":"J. Inorg. Biochem."},{"key":"2026083119150848700_cit26","first-page":"333","article-title":"Die Kinetik Der\nInvertinwirkung","volume":"49","author":"Michaelis","year":"1913","journal-title":"Biochem. Z."},{"key":"2026083119150848700_cit27","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1016\/0005-2744(69)90420-3","article-title":"Tight-Binding\nInhibitor Kinetics","volume":"185","author":"Morrison","year":"1969","journal-title":"Biochim. Biophys. Acta"},{"key":"2026083119150848700_cit28","first-page":"iv","article-title":"Hemoglobin\nDissociation Curves","volume":"40","author":"Hill","year":"1910","journal-title":"J. Physiol."},{"key":"2026083119150848700_cit29","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1107\/S0907444909052925","article-title":"PHENIX\nSoftware for Structure Solution","volume":"66","author":"Adams","year":"2010","journal-title":"Acta Crystallographica\nD"},{"key":"2026083119150848700_cit30","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1107\/S2052252514009324","article-title":"PDB_REDO\nServer","volume":"1","author":"Joosten","year":"2014","journal-title":"IUCrJ."},{"issue":"Pt 4","key":"2026083119150848700_cit31","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1107\/S0907444910007493","article-title":"Features and\nDevelopment\nof Coot","volume":"66","author":"Emsley","year":"2010","journal-title":"Acta Crystallogr. D Biol. Crystallogr."},{"issue":"4","key":"2026083119150848700_cit32","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1124\/dmd.106.012609","article-title":"Visible\nSpectra of Type II Cytochrome\nP450-Drug Complexes: Evidence That \u201cIncomplete\u201d Heme\nCoordination Is Common","volume":"35","author":"Locuson","year":"2007","journal-title":"Drug Metab. Dispos."},{"issue":"1","key":"2026083119150848700_cit33","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1111\/j.1742-7843.2006.pto_437.x","article-title":"Pioglitazone Is\nMetabolised by CYP2C8 and CYP3A4 in Vitro: Potential for Interactions\nwith CYP2C8 Inhibitors","volume":"99","author":"Jaakkola","year":"2006","journal-title":"Basic Clin. Pharmacol.\nToxicol."},{"issue":"25","key":"2026083119150848700_cit34","doi-asserted-by":"publisher","first-page":"17227","DOI":"10.1074\/jbc.M802180200","article-title":"Determinants of\nCytochrome P450 2C8 Substrate Binding:\nStructures of Complexes with Montelukast, Troglitazone, Felodipine,\nand 9-Cis-Retinoic Acid","volume":"283","author":"Schoch","year":"2008","journal-title":"J. Biol. Chem."},{"issue":"7","key":"2026083119150848700_cit35","doi-asserted-by":"publisher","first-page":"1113","DOI":"10.1021\/tx200110h","article-title":"Toxic Metabolite Formation from Troglitazone: New Insights\nfrom a DFT Study","volume":"24","author":"Dixit","year":"2011","journal-title":"Chem. Res. Toxicol."},{"issue":"2","key":"2026083119150848700_cit36","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.canlet.2004.10.007","article-title":"Cytochrome\nP450-Mediated Metabolism\nof Estrogens and Its Regulation in Human","volume":"227","author":"Tsuchiya","year":"2005","journal-title":"Cancer\nLett."},{"issue":"7","key":"2026083119150848700_cit37","doi-asserted-by":"publisher","first-page":"772","DOI":"10.1016\/S0090-9556(24)15347-0","article-title":"Absorption, Disposition,\nand Metabolism\nof Rosiglitazone in Humans","volume":"28","author":"Cox","year":"2000","journal-title":"Drug Metab. Dispos."},{"issue":"45","key":"2026083119150848700_cit38","doi-asserted-by":"publisher","first-page":"13456","DOI":"10.1021\/bi011197q","article-title":"Pivotal Role of\nWater in the Mechanism of P450BM-3","volume":"40","author":"Haines","year":"2001","journal-title":"Biochemistry"},{"issue":"4","key":"2026083119150848700_cit39","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1124\/mi.3.4.194","article-title":"Cytochromes\nP450, Drugs, and Diseases","volume":"3","author":"Guengerich","year":"2003","journal-title":"Mol. Interv."},{"issue":"5","key":"2026083119150848700_cit40","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1007\/s40262-013-0041-1","article-title":"Developmental Changes\nin Cytochrome P450 3A Isoforms","volume":"52","author":"Ince","year":"2013","journal-title":"Clin. Pharmacokinet."},{"issue":"4","key":"2026083119150848700_cit41","doi-asserted-by":"publisher","first-page":"528","DOI":"10.1046\/j.1365-2125.1999.00044.x","article-title":"Identification of Human Cytochrome P450 Enzymes in\nArtemisinin Metabolism","volume":"48","author":"Svensson","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"issue":"3","key":"2026083119150848700_cit42","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1046\/j.1365-2125.1999.00030.x","article-title":"Cytochrome P450 Enzymes in Rosiglitazone\nMetabolism","volume":"48","author":"Baldwin","year":"1999","journal-title":"Br. J. Clin. Pharmacol."},{"issue":"7","key":"2026083119150848700_cit43","doi-asserted-by":"publisher","first-page":"1279","DOI":"10.1124\/dmd.112.045286","article-title":"Repaglinide\nMetabolic Pathways and\nEnzyme Contribution","volume":"40","author":"Sall","year":"2012","journal-title":"Drug Metab. Dispos."},{"issue":"3","key":"2026083119150848700_cit44","doi-asserted-by":"publisher","first-page":"305","DOI":"10.1046\/j.0306-5251.2003.01862.x","article-title":"CYP2C8\nand CYP3A4 in Repaglinide","volume":"56","author":"Bidstrup","year":"2003","journal-title":"Br. J. Clin. Pharmacol."},{"issue":"4","key":"2026083119150848700_cit45","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1021\/tx9701687","article-title":"Oxidation of Acetaminophen by Human\nCytochromes P450 2E1 and 2A6","volume":"11","author":"Chen","year":"1998","journal-title":"Chem. Res. Toxicol."},{"issue":"1","key":"2026083119150848700_cit46","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-41854-2","article-title":"Efficacy and Safety\nof Pioglitazone Monotherapy in Type 2 Diabetes Mellitus: A Systematic\nReview and Meta-Analysis of Randomised Controlled Trials","volume":"9","author":"Alam","year":"2019","journal-title":"Sci. Rep."},{"issue":"7122","key":"2026083119150848700_cit47","doi-asserted-by":"publisher","first-page":"1559","DOI":"10.1136\/bmj.315.7122.1559n","article-title":"Diabetes Drug\nWithdrawn after Reports of Hepatic Events","volume":"315","author":"Wise","year":"1997","journal-title":"BMJ"},{"issue":"No. 113","key":"2026083119150848700_cit48","first-page":"29","article-title":"Thiazolidinedione\nHepatotoxicity: A Class Effect?","author":"Tolman","year":"2000","journal-title":"Int. J. Clin.\nPract. Suppl."},{"issue":"10","key":"2026083119150848700_cit49","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2024.107799","article-title":"Development of a High Throughput Cytochrome P450 Ligand-Binding\nAssay","volume":"300","author":"Frydendall","year":"2024","journal-title":"J. Biol. 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