Knockout of cytochrome P450 3A yields new mouse models for understanding xenobiotic metabolism
Open accessAbstract
Cytochrome P450 3A (CYP3A) enzymes constitute an important detoxification system that contributes to primary metabolism of more than half of all prescribed medications.To investigate the physiological and pharmacological roles of CYP3A, we generated Cyp3a-knockout (Cyp3a -/-) mice lacking all functional Cyp3a genes.Cyp3a -/-mice were viable, fertile, and without marked physiological abnormalities.However, these mice exhibited severely impaired detoxification capacity when exposed to the chemotherapeutic agent docetaxel, displaying higher exposure levels in response to both oral and intravenous administration.These mice also demonstrated increased sensitivity to docetaxel toxicity, suggesting a primary role for Cyp3a in xenobiotic detoxification.To determine the relative importance of intestinal versus hepatic Cyp3a in first-pass metabolism, we generated transgenic Cyp3a -/-mice expressing human CYP3A4 in either the intestine or the liver.Expression of CYP3A4 in the intestine dramatically decreased absorption of docetaxel into the bloodstream, while hepatic expression aided systemic docetaxel clearance.These results suggest that CYP3A expression determines impairment of drug absorption and efficient systemic clearance in a tissue-specific manner.The genetic models used in this study provide powerful tools to further study CYP3A-mediated xenobiotic metabolism, as well as interactions between CYP3A and other detoxification systems.Nonstandard abbreviations used: AUC, area under the curve; Cyp3a, cytochrome P450 3A; Cyp3a -/-A mice, Cyp3a-knockout mice with apoE promoter-driven liverspecific expression of human CYP3A4; Cyp3a -/-V mice, Cyp3a -/-mice with villin promoter-driven intestine-specific expression of human CYP3A4; P-gp, P-glycoprotein.
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?
Mitotane is a very strong inducer of the drug-metabolizing microsomal liver and gut enzyme CYP3A4.
“It has recently become clear that mitotane is a very strong inducer of the drug-metabolizing microsomal liver and gut enzyme CYP3A4 (299, 301–303).”
From Adrenocortical carcinoma (2014) · cites this paper as [303]
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
Kuehl, P. M., Zhang, J., Lin, Y., Lamba, J. K., Assem, M., Schuetz, J. D., Watkins, P. B., Daly, A. K., Wrighton, S. A., Hall, S. D., et al. (2001) · Nature Genetics · doi:10.1038/86882 · Cited by 2,162 · see citing works
CYTOCHROME P-450 3A4: Regulation and Role in Drug Metabolism
Guengerich, F. P. (1999) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.39.1.1 · Cited by 1,271 · see citing works
Drug Metabolism and Variability among Patients in Drug Response
Wilkinson, G. R. (2005) · New England Journal of Medicine · doi:10.1056/nejmra032424 · Cited by 1,185 · see citing works
Nelson, D. R., Zeldin, D. C., Hoffman, S. M. G., Maltais, L. J., Wain, H., & Nebert, D. W. (2003) · Pharmacogenetics · doi:10.1097/00008571-200401000-00001 · Cited by 1,023 · see citing works
Genetic contribution to variable human CYP3A-mediated metabolism
Lamba, J. K., Lin, Y. S., Schuetz, E. G., & Thummel, K. E. (2002) · Advanced Drug Delivery Reviews · doi:10.1016/s0169-409x(02)00066-2 · Cited by 987 · see citing works
Dresser, G. K., Spence, J. D., & Bailey, D. G. (2000) · Clinical Pharmacokinetics · doi:10.2165/00003088-200038010-00003 · Cited by 908 · see citing works
Wacher, V. J., Wu, C., & Benet, L. Z. (1995) · Molecular Carcinogenesis · doi:10.1002/mc.2940130302 · Cited by 862 · see citing works
Bruno, R., Hille, D. A., Riva, A., Vivier, N., Huinink, W. W. T. B., van Oosterom, A. T., Kaye, S. B., Verweij, J., Fossella, F. V., Valero, V., et al. (1998) · Journal of Clinical Oncology · doi:10.1200/jco.1998.16.1.187 · Cited by 424 · see citing works
Is the Role of the Small Intestine in First-Pass Metabolism Overemphasized?
Lin, J. H., Chiba, M., & Baillie, T. A. (1999) · Pharmacological Reviews · doi:10.1016/s0031-6997(24)01402-9 · Cited by 354 · see citing works
Interindividual Variability and Tissue-Specificity in the Expression of Cytochrome P450 3A mRNA
Koch, I., Weil, R., Wolbold, R., Brockmöller, J., Hustert, E., Burk, O., Nussler, A. K., Neuhaus, P., Eichelbaum, M. F., Zanger, U. M., et al. (2002) · Drug Metabolism and Disposition · doi:10.1124/dmd.30.10.1108 · Cited by 310 · see citing works
Molecular and physical mechanisms of first-pass extraction.
Hall, S. D., Thummel, K. E., Watkins, P. B., Lown, K. S., Benet, L. Z., Paine, M. F., Mayo, R. R., Turgeon, D. K., Bailey, D. G., Fontana, R. J., et al. (1999) · PubMed · Cited by 236 · see citing works
Jonker, J. W., Wagenaar, E., Mol, C. A. A. M., Buitelaar, M., Koepsell, H., Smit, J. W., & Schinkel, A. H. (2001) · Molecular and Cellular Biology · doi:10.1128/mcb.21.16.5471-5477.2001 · Cited by 227 · see citing works
Self-citationMarre, F., Sanderink, G., de Sousa, G., et al. (1996) · PubMed · Cited by 221 · see citing works
Megabase deletions of gene deserts result in viable mice
Nóbrega, M. A., Zhu, Y., Plajzer-Frick, I., Afzal, V., & Rubin, E. M. (2004) · Nature · doi:10.1038/nature03022 · Cited by 214 · see citing works
The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.
Hirth, J. A., Watkins, P. B., Strawderman, M. S., Schott, A. F., Bruno, R., & Baker, L. H. (2000) · PubMed · Cited by 201 · see citing works
Shou, M., Martinet, M., Korzekwa, K. R., et al. (1998) · Pharmacogenetics · doi:10.1097/00008571-199810000-00004 · Cited by 190 · see citing works
Kitada, M., Kamataki, T., Itahashi, K., Rikihisa, T., & Kanakubo, Y. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)76460-6 · Cited by 162 · see citing works
Galetin, A., & Houston, J. B. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.106013 · Cited by 155 · see citing works
Bardelmeijer, H. A., Ouwehand, M., Buckle, T., et al. (2002) · PubMed · Cited by 135 · see citing works
CYP3A5genotype predicts renal CYP3A activity and blood pressure in healthy adults
Givens, R. C., Lin, Y. S., Dowling, A. L. S., et al. (2003) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00322.2003 · Cited by 132 · see citing works
Potential for improvement of docetaxel-based chemotherapy: a pharmacological review
Engels, F. K., Sparreboom, A., Mathôt, R. A. A., et al. (2005) · British Journal of Cancer · doi:10.1038/sj.bjc.6602698 · Cited by 111 · see citing works
Symposium Article: Molecular and Physical Mechanisms of First-Pass Extraction
Hall, S. D., Thummel, K. E., Watkins, P. B., Lown, K. S., Benet, L. Z., Paine, M. F., Mayo, R. R., Turgeon, D. K., Bailey, D. G., Fontana, R. J., et al. (1999) · Drug Metabolism and Disposition · doi:10.1016/s0090-9556(24)15271-3 · Cited by 109 · see citing works
Association Between the CYP3A5 Genotype and Blood Pressure
Ho, H., Pinto, A. G., Hall, S. D., et al. (2005) · Hypertension · doi:10.1161/01.hyp.0000151361.31736.96 · Cited by 85 · see citing works
Emoto, C., Yamazaki, H., Yamasaki, S., Shimada, T., Nakajima, M., & Yokoi, T. (2000) · Xenobiotica · doi:10.1080/00498250050200104 · Cited by 65 · see citing works
Kuppens, I. E. L. M., van Maanen, M. J., Rosing, H., et al. (2004) · Biomedical Chromatography · doi:10.1002/bmc.457 · Cited by 58 · see citing works
Self-citationHormonal regulation of the zonated expression of cytochrome P-450 3A in rat liver
Oinonen, T., & Lindros, K. O. (1995) · Biochemical Journal · doi:10.1042/bj3090055 · Cited by 54 · see citing works
van Herwaarden, A. E., Smit, J. W., Sparidans, R. W., et al. (2005) · Drug Metabolism and Disposition · doi:10.1124/dmd.105.004721 · Cited by 44 · see citing works
Self-citationCorticosterone 6 beta-hydroxylase in A6 epithelia: a steroid-inducible cytochrome P-450
Grogan, W. M., Phillips, V., Schuetz, E. G., et al. (1990) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1990.258.3.c480 · Cited by 24 · see citing works
Lieb, W., Bolbrinker, J., Döring, A., et al. (2006) · Clinical Science · doi:10.1042/cs20060075 · Cited by 14 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Else, T., Kim, A. C., Sabolch, A., Raymond, V. M., Kandathil, A., Caoili, E. M., Jolly, S., Miller, B. S., Giordano, T. J., & Hammer, G. D. (2014) · Endocrine Reviews · doi:10.1210/er.2013-1029 · Cited by 892 · see citing works
Human cytochromes P450 in health and disease
Nebert, D. W., Wikvall, K., & Miller, W. L. (2013) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2012.0431 · Cited by 505 · see citing works
Komura, H., & Iwaki, M. (2011) · Drug Metabolism Reviews · doi:10.3109/03602532.2011.597401 · Cited by 78 · see citing works
- Authors
- van Herwaarden, A. E., Wagenaar, E., van der Kruijssen, C. M. M., van Waterschoot, R. A. B., Smit, J. W., Song, J.-Y., van der Valk, M. A., van Tellingen, O., van der Hoorn, J. W. A., Rosing, H., Beijnen, J. H., & Schinkel, A. H.
- Affiliations
- The Netherlands Cancer Institute (NL)
- Slotervaartziekenhuis (NL)
- Corresponding author
- Schinkel, Alfred H.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-11-01
- Volume
- 117
- Issue
- 11
- Pages
- 3583-3592
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2045619
- OpenAlex
- W2150549589
- Cited by
- 235
- References
- 29
- Citations by year
- 2025: 8 · 2024: 7 · 2023: 7 · 2022: 10 · 2021: 17 · 2020: 12 · 2019: 12 · 2018: 9 · 2017: 11 · 2016: 17 · 2015: 12 · 2014: 13 · 2013: 16 · 2012: 14
- FWCI
- 14.69
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- TNO Repository (submittedVersion)
- Funders
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek
- KWF Kankerbestrijding
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- CYP3A, CYP3A4, xenobiotic metabolism, docetaxel, drug detoxification, drug absorption, first-pass metabolism, drug clearance, drug toxicity, tissue-specific gene expression, P-glycoprotein
- MeSH terms
- Docetaxel, Animals, Antineoplastic Agents, Biological Availability, Cytochrome P-450 Enzyme System, Humans, Membrane Proteins, Mice, Transgenic, Microsomes, Phenotype, Xenobiotics, Mice, Knockout, Taxoids, Mice, Cytochrome P-450 CYP3A
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
