Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes
Open accessAbstract
Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4alpha, as mediators of the sex-dependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
There is established sexual dimorphism in liver metabolism.
“Consistent with established sexual dimorphism in liver metabolism64”
From Constitutive Androstane Receptor Regulates Bile Acid Homeostasis and Metabolism During Liver Regeneration (2026) · cites this paper as [64]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Circadian Rhythms: Mechanisms and Therapeutic Implications
Levi, F., & Schibler, U. (2007) · Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.47.120505.105208 · Cited by 645 · see citing works
Tissue-specific transcriptional regulation has diverged significantly between human and mouse
Odom, D. T., Dowell, R. D., Jacobsen, E. S., Gordon, W., Danford, T. W., MacIsaac, K. D., Rolfe, P. A., Conboy, C. M., Gifford, D. K., & Fraenkel, E. (2007) · Nature Genetics · doi:10.1038/ng2047 · Cited by 506 · see citing works
Inactivation by UDP-glucuronosyltransferase enzymes: The end of androgen signaling
Chouinard, S., Yueh, M.-F., Tukey, R. H., Giton, F., Fiet, J., Pelletier, G., Barbier, O., & Bélanger, A. (2008) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2008.03.016 · Cited by 90 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Laz EV, Sugathan A and Waxman DJ (2009) Dynamic in vivo binding of STAT5 to growth hormone-regulated genes in intact rat liver. Sex-specific binding at low but not high affinity STAT5 sites. Mol Endocrinol doi: 10.1210/me.2008-0449. · DOI
Cited by
Sorted by citations
Zanger, U. M., & Schwab, M. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2012.12.007 · Cited by 4,169 · see citing works
Metabolism disrupting chemicals and metabolic disorders
Heindel, J. J., Blumberg, B., Cave, M., Machtinger, R., Mantovani, A., Mendez, M. A., Nadal, A., Palanza, P., Panzica, G., Sargis, R., et al. (2017) · Reproductive Toxicology · doi:10.1016/j.reprotox.2016.10.001 · Cited by 1,101 · see citing works
Organotypic liver culture models: meeting current challenges in toxicity testing
LeCluyse, E. L., Witek, R. P., Andersen, M. E., & Powers, M. J. (2012) · Critical Reviews in Toxicology · doi:10.3109/10408444.2012.682115 · Cited by 363 · see citing works
Gabory, A., Roseboom, T. J., Moore, T., Moore, L. G., & Junien, C. (2013) · Biology of Sex Differences · doi:10.1186/2042-6410-4-5 · Cited by 344 · see citing works
Liver zonation: Novel aspects of its regulation and its impact on homeostasis
Gebhardt, R. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i26.8491 · Cited by 275 · see citing works
Let’s talk about sex: Differences in drug therapy in males and females
Madla, C. M., Gavins, F. K. H., Merchant, H. A., Orlu, M., Murdan, S., & Basit, A. W. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.05.014 · Cited by 167 · see citing works
Identification and Application of Gene Expression Signatures Associated with Lifespan Extension
Tyshkovskiy, A., Bozaykut, P., Borodinova, A. A., Gerashchenko, M. V., Ables, G. P., Garratt, M., Khaitovich, P., Clish, C. B., Miller, R. A., & Gladyshev, V. N. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.018 · Cited by 167 · see citing works
Estrogen as a key regulator of energy homeostasis and metabolic health
Mahboobifard, F., Pourgholami, M. H., Jorjani, M., Dargahi, L., Amiri, M., Sadeghi, S., & Tehrani, F. R. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.113808 · Cited by 154 · see citing works
Sex Differences in the Expression of Drug-Metabolizing and Transporter Genes in Human Liver
Yang, L., & Li, Y. (2012) · Journal of Drug Metabolism & Toxicology · doi:10.4172/2157-7609.1000119 · Cited by 135 · see citing works
Bhargava, A., Arnold, A. P., Bangasser, D. A., Denton, K. M., Gupta, A., Hilliard Krause, L. M., Mayer, E. A., McCarthy, M., Miller, W. L., Raznahan, A., et al. (2021) · Endocrine Reviews · doi:10.1210/endrev/bnaa034 · Cited by 130 · see citing works
Thyroid Hormone Signaling and Homeostasis During Aging
Bowers, J., Terrien, J., Clerget-Froidevaux, M. S., Gothié, J. D., Rozing, M. P., Westendorp, R. G. J., van Heemst, D., & Demeneix, B. A. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1056 · Cited by 117 · see citing works
Attanasio, R. (2019) · Environmental Pollution · doi:10.1016/j.envpol.2019.113061 · Cited by 72 · see citing works
Eliot, L., & Richardson, S. S. (2016) · The Journal of Neuroscience · doi:10.1523/jneurosci.1391-16.2016 · Cited by 70 · see citing works
Biological sex differences in pharmacokinetics and adverse drug reactions
Aljohmani, A., & Yildiz, D. (2026) · Naunyn-Schmiedeberg's Archives of Pharmacology · doi:10.1007/s00210-025-04721-8 · Cited by 35 · see citing works
Modelling female physiology from head to Toe: impact of sex hormones, menstrual cycle, and pregnancy
Abo, S., Smith, D., Stadt, M., & Layton, A. (2022) · Journal of Theoretical Biology · doi:10.1016/j.jtbi.2022.111074 · Cited by 35 · see citing works
Psychophysiological stress: a significant parameter in drug pharmacokinetics
Konstandi, M. (2013) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425255.2013.816283 · Cited by 31 · see citing works
ESRP2–microRNA-122 axis promotes the postnatal onset of liver polyploidization and maturation
Bangru, S., Chen, J., Baker, N., Das, D., Chembazhi, U. V., Derham, J. M., Chorghade, S., Arif, W., Alencastro, F., Duncan, A. W., et al. (2025) · Genes & Development · doi:10.1101/gad.352129.124 · Cited by 4 · see citing works
Zhou, W., Chembazhi, U. V., Huang, J., Bangru, S., Dean, A. E., Asokakumar, A., Kalsotra, A., Rudnick, D. A., & Anakk, S. (2026) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2026.101858
- Authors
- Waxman, D. J., & Holloway, M. G.
- Affiliations
- Boston University (US)
- ORCID
- Waxman, David J.
- Venue
- Molecular Pharmacology
- Publisher
- Elsevier BV
- Published
- 2009-08
- Volume
- 76
- Issue
- 2
- Pages
- 215-228
- ISSN
- 0026-895X (ISSN-L)
- PMC
- PMC2713118
- OpenAlex
- W2118247434
- Cited by
- 815
- References
- 3
- Citations by year
- 2026: 59 · 2025: 56 · 2024: 55 · 2023: 41 · 2022: 45 · 2021: 55 · 2020: 68 · 2019: 37 · 2018: 43 · 2017: 53 · 2016: 43 · 2015: 52 · 2014: 30 · 2013: 54 · 2012: 49
- FWCI
- 5.38
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Pharmacology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-33765)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Sex and Gender in Healthcare
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- sex differences, hepatic drug metabolism, cytochrome P450, CYP3A4, growth hormone, STAT5B, HNF4α, sexual dimorphism, hepatic gene expression, sulfotransferase, glutathione S-transferase, UDP-glucuronosyltransferase, growth hormone pulsatility, xenobiotic metabolism
- MeSH terms
- Animals, Female, Gene Expression Regulation, Humans, Liver, Male, Models, Biological, Sex Characteristics
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
