{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T03:15:20Z","timestamp":1778814920300,"version":"3.51.4"},"reference-count":52,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T00:00:00Z","timestamp":1628812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Individual response to drugs is highly variable and largely influenced by genetic variants and gene-expression profiles. In addition, it has been shown that response to drugs is strongly sex-dependent, both in terms of efficacy and toxicity. To expand current knowledge on sex differences in the expression of genes relevant for drug response, we generated a catalogue of differentially expressed human transcripts encoded by 289 genes in 41 human tissues from 838 adult individuals of the Genotype-Tissue Expression project (GTEx, v8 release) and focused our analysis on relevant transcripts implicated in drug response. We detected significant sex-differentiated expression of 99 transcripts encoded by 59 genes in the tissues most relevant for human pharmacology (liver, lung, kidney, small intestine terminal ileum, skin not sun-exposed, and whole blood). Among them, as expected, we confirmed significant differences in the expression of transcripts encoded by the cytochromes in the liver, CYP2B6, CYP3A7, CYP3A5, and CYP1A1. Our systematic investigation on differences between male and female in the expression of drug response-related genes, reinforce the need to overcome the sex bias of clinical trials.<\/jats:p>","DOI":"10.3390\/biom11081206","type":"journal-article","created":{"date-parts":[[2021,8,13]],"date-time":"2021-08-13T09:22:38Z","timestamp":1628846558000},"page":"1206","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Sex-Biased Expression of Pharmacogenes across Human Tissues"],"prefix":"10.3390","volume":"11","author":[{"given":"Maria Laura","family":"Idda","sequence":"first","affiliation":[{"name":"Institute of Genetics and Biomedical research, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1681-6448","authenticated-orcid":false,"given":"Ilaria","family":"Campesi","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giovanni","family":"Fiorito","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"},{"name":"Unit of Environmental Epidemiology, School of Public Health, Imperial College, London SW7 2AZ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9326-5280","authenticated-orcid":false,"given":"Andrea","family":"Vecchietti","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvana Anna Maria","family":"Urru","sequence":"additional","affiliation":[{"name":"Hospital Pharmacy Unit, Trento General Hospital, Autonomous Province of Trento, 38122 Trento, Italy"},{"name":"Department of Chemistry and Pharmacy, School of Hospital Pharmacy, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2174-0983","authenticated-orcid":false,"given":"Maria Giuliana","family":"Solinas","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavia","family":"Franconi","sequence":"additional","affiliation":[{"name":"National Laboratory of Pharmacology and Gender medicine, National Institute of Biostructure and Biosystems, 00136 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4385-9336","authenticated-orcid":false,"given":"Matteo","family":"Floris","sequence":"additional","affiliation":[{"name":"Institute of Genetics and Biomedical research, 07100 Sassari, Italy"},{"name":"Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,13]]},"reference":[{"key":"ref_1","first-page":"191","article-title":"Personalized Medicine: A Tailor Made Medicine","volume":"6","author":"Akhondzadeh","year":"2014","journal-title":"Avicenna J. Med. Biotechnol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/tpj.2012.45","article-title":"Pharmacogenomics of drug-metabolizing enzymes: A recent update on clinical implications and endogenous effects","volume":"13","author":"Sim","year":"2013","journal-title":"Pharmacogenom. J."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"EUGenMed Cardiovascular Clinical Study Group, Regitz-Zagrosek, V., Oertelt-Prigione, S., Prescott, E., Franconi, F., Gerdts, E., Foryst-Ludwig, A., Maas, A.H., Kautzky-Willer, A., and Knappe-Wegner, D. (2016). Gender in Cardiovascular Diseases: Impact on Clinical Manifestations, Management, and Outcomes. Eur. Heart J., 37, 24\u201334.","DOI":"10.1093\/eurheartj\/ehv598"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2561","DOI":"10.2174\/0929867323666161003124616","article-title":"Sex Impact on Biomarkers, Pharmacokinetics and Pharmacodynamicsv","volume":"24","author":"Franconi","year":"2017","journal-title":"Curr. Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1000119","DOI":"10.4172\/2157-7609.1000119","article-title":"Sex Differences in the Expression of Drug-Metabolizing and Transporter Genes in Human Liver","volume":"3","author":"Yang","year":"2012","journal-title":"J. Drug Metab. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.phrs.2017.01.023","article-title":"Sex-gender-related therapeutic approaches for cardiovascular complications associated with diabetes","volume":"119","author":"Campesi","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.pharmthera.2012.12.007","article-title":"Cytochrome P450 Enzymes in Drug Metabolism: Regulation of Gene Expression, Enzyme Activities, and Impact of Genetic Variation","volume":"138","author":"Zanger","year":"2013","journal-title":"Pharmacol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1111\/j.1365-2125.2007.03029.x","article-title":"Identifying how age and gender influence prescription drug use in a primary health care environment in Catalonia, Spain","volume":"65","author":"Modamio","year":"2008","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Orlando, V., Mucherino, S., Guarino, I., Guerriero, F., Trama, U., and Menditto, E. (2020). Gender Differences in Medication Use: A Drug Utilization Study Based on Real World Data. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17113926"},{"key":"ref_10","first-page":"435","article-title":"Comparative kinetics and response to the benzodiazepine agonists triazolam and zolpidem: Evaluation of sex-dependent differences","volume":"293","author":"Greenblatt","year":"2000","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1046\/j.0306-5251.2003.01852.x","article-title":"Pharmacokinetic properties of zolpidem in elderly and young adults: Possible modulation by testosterone in men","volume":"56","author":"Olubodun","year":"2003","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1002\/jcph.220","article-title":"Gender differences in pharmacokinetics and pharmacodynamics of zolpidem following sublingual administration","volume":"54","author":"Greenblatt","year":"2014","journal-title":"J. Clin. Pharmacol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"113804","DOI":"10.1016\/j.addr.2021.05.014","article-title":"Let\u2019s talk about sex: Differences in drug therapy in males and females","volume":"175","author":"Madla","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"730","DOI":"10.1124\/pharmrev.120.000206","article-title":"Sex- and Gender-Based Pharmacological Response to Drugs","volume":"73","author":"Berthold","year":"2021","journal-title":"Pharmacol. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1007\/s00228-003-0651-x","article-title":"Pregnancy and use of oral contraceptives reduces the biotransformation of proguanil to cycloguanil","volume":"59","author":"McGready","year":"2003","journal-title":"Eur. J. Clin. Pharmacol."},{"key":"ref_16","first-page":"131","article-title":"CYP2D6 polymorphisms and their influence on risperidone treatment","volume":"9","author":"Puangpetch","year":"2016","journal-title":"Pharmgenomics Pers. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1007\/s10928-020-09698-w","article-title":"Drug dosing during pregnancy\u2014opportunities for physiologically based pharmacokinetic models","volume":"47","author":"Abduljalil","year":"2020","journal-title":"J. Pharmacokinet. Pharmacodyn."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1365-2125.2001.01328.x","article-title":"Influence of gender and oral contraceptives on CYP2D6 and CYP2C19 activity in healthy volunteers","volume":"51","author":"Spigset","year":"2001","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"650904","DOI":"10.3389\/fpsyt.2021.650904","article-title":"The Pharmacodynamics of Antipsychotic Drugs in Women and Men","volume":"12","author":"Seeman","year":"2021","journal-title":"Front. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.coph.2021.06.007","article-title":"Type 2 diabetic women are not small type 2 diabetic men: Sex-and-gender differences in antidiabetic drugs","volume":"60","author":"Campesi","year":"2021","journal-title":"Curr. Opin. Pharmacol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Campesi, I., Racagni, G., and Franconi, F. (2021). Just a Reflection: Does Drug Repurposing Perpetuate Sex-Gender Bias in the Safety Profile?. Pharmaceuticals, 14.","DOI":"10.3390\/ph14080730"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"The GTEx Consortium (2020). The GTEx Consortium Atlas of Genetic Regulatory Effects across Human Tissues. Science, 369, 1318\u20131330.","DOI":"10.1126\/science.aaz1776"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1093\/bioinformatics\/bts034","article-title":"The sva package for removing batch effects and other unwanted variation in high-throughput experiments","volume":"28","author":"Leek","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/clpt.2012.96","article-title":"Pharmacogenomics Knowledge for Personalized Medicine","volume":"92","author":"McDonagh","year":"2012","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"D668","DOI":"10.1093\/nar\/gkj067","article-title":"Drugbank: A comprehensive resource for in silico drug discovery and exploration","volume":"34","author":"Wishart","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eaba3066","DOI":"10.1126\/science.aba3066","article-title":"The Impact of Sex on Gene Expression across Human Tissues","volume":"369","author":"Oliva","year":"2020","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1007\/s12272-021-01306-w","article-title":"Biological roles of cytochrome P450 1A1, 1A2, and 1B1 enzymes","volume":"44","author":"Kwon","year":"2021","journal-title":"Arch. Pharmacal Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1038\/nature19771","article-title":"XPO1-Dependent Nuclear Export Is a Druggable Vulnerability in KRAS-Mutant Lung Cancer","volume":"538","author":"Kim","year":"2016","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.cell.2017.09.027","article-title":"Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma","volume":"171","author":"Reddy","year":"2017","journal-title":"Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"5785","DOI":"10.1074\/jbc.275.8.5785","article-title":"Structures, Enzymatic Properties, and Expression of Novel Human and Mouse Secretory Phospholipase A2s","volume":"275","author":"Suzuki","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"5768","DOI":"10.1016\/S0021-9258(18)83616-X","article-title":"Structure and Properties of a Human Non-Pancreatic Phospholipase A2","volume":"264","author":"Kramer","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1080\/03602530802431439","article-title":"The Aldo-Keto Reductase Superfamily and its Role in Drug Metabolism and Detoxification","volume":"40","author":"Barski","year":"2008","journal-title":"Drug Metab. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1001\/jamainternmed.2019.7194","article-title":"Clinical Advances in Sex- and Gender-Informed Medicine to Improve the Health of All: A Review","volume":"180","author":"Bartz","year":"2020","journal-title":"JAMA Intern. Med."},{"key":"ref_35","first-page":"188","article-title":"Identification and analysis of the human sex-biased genes","volume":"19","author":"Guo","year":"2018","journal-title":"Brief. Bioinform."},{"key":"ref_36","unstructured":"(2021, August 13). Available online: https:\/\/doi.org\/10.5281\/zenodo.3939042."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1097\/00008571-200007000-00005","article-title":"Two Linked Mutations in Transcriptional Regulatory Elements of the CYP3A5 Gene Constitute the Major Genetic Determinant of Polymorphic Activity in Humans","volume":"10","author":"Paulussen","year":"2000","journal-title":"Pharmacogenetics"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"598","DOI":"10.2174\/138920008785821710","article-title":"CYP2B6: New Insights into a Historically Overlooked Cytochrome P450 Isozyme","volume":"9","author":"Wang","year":"2008","journal-title":"Curr. Drug Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1101\/gr.103341.109","article-title":"Systematic genetic and genomic analysis of cytochrome P450 enzyme activities in human liver","volume":"20","author":"Yang","year":"2010","journal-title":"Genome Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2165\/00003088-200544010-00002","article-title":"The Influence of Age and Sex on the Clearance of Cytochrome P450 3A Substrates","volume":"44","author":"Cotreau","year":"2005","journal-title":"Clin. Pharmacokinet."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1124\/jpet.103.054866","article-title":"Hepatic CYP2B6 Expression: Gender and Ethnic Differences and Relationship to CYP2B6 Genotype and CAR (Constitutive Androstane Receptor) Expression","volume":"307","author":"Lamba","year":"2003","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1124\/mol.109.056705","article-title":"Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes","volume":"76","author":"Waxman","year":"2009","journal-title":"Mol. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1007\/BF02369901","article-title":"Characterization of the promoter region of human steroid sulfatase: A gene which escapes X inactivation","volume":"22","author":"Li","year":"1996","journal-title":"Somat. Cell Mol. Genet"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1046\/j.1471-4159.2004.02336.x","article-title":"Steroid Sulfatase (STS) Expression in the Human Temporal Lobe: Enzyme Activity, MRNA Expression and Immunohistochemistry Study","volume":"89","author":"Steckelbroeck","year":"2004","journal-title":"J. Neurochem."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3365","DOI":"10.1210\/en.2018-00531","article-title":"Sex-Dimorphic and Sex Hormone\u2013Dependent Role of Steroid Sulfatase in Adipose Inflammation and Energy Homeostasis","volume":"159","author":"Bi","year":"2018","journal-title":"Endocrinology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"T199","DOI":"10.1530\/JME-17-0219","article-title":"Sulfation Pathways: The Steroid Sulfate Axis and Its Relationship to Maternal Behaviour and Mental Health","volume":"61","author":"Davies","year":"2018","journal-title":"J. Mol. Endocrinol."},{"key":"ref_47","unstructured":"McQueen, C.A. (2010). 6.26\u2014aldehydes and cardiovascular disease. Comprehensive Toxicology, Elsevier. [2nd ed.]."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"808","DOI":"10.3389\/fgene.2020.00808","article-title":"Gender Differential Transcriptome in Gastric and Thyroid Cancers","volume":"11","author":"Sousa","year":"2020","journal-title":"Front. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"349","DOI":"10.2165\/00128071-200102060-00001","article-title":"Do Women Have More Adverse Drug Reactions?","volume":"2","author":"Rademaker","year":"2001","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_50","unstructured":"(2021, August 13). Available online: https:\/\/academic.oup.com\/nargab\/article\/2\/1\/lqz010\/5609475#209718189."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1016\/j.phrs.2016.08.014","article-title":"Sex-Specific Pharmacological Modulation of Autophagic Process in Human Umbilical Artery Smooth Muscle","volume":"113","author":"Campesi","year":"2016","journal-title":"Cells Pharmacol. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"173762","DOI":"10.1016\/j.ejphar.2020.173762","article-title":"Combined Oral Contraceptives Modify the Effect of Smoking on Inflammatory Cellular Indexes and Endothelial Function in Healthy Subjects","volume":"891","author":"Campesi","year":"2021","journal-title":"Eur. J. Pharmacol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/8\/1206\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:45:31Z","timestamp":1760165131000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/11\/8\/1206"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,13]]},"references-count":52,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,8]]}},"alternative-id":["biom11081206"],"URL":"https:\/\/doi.org\/10.3390\/biom11081206","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202106.0675.v1","asserted-by":"object"}]},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,13]]}}}