Variation in human gut microbiota impacts tamoxifen pharmacokinetics
ABSTRACT Tamoxifen is the most prescribed drug used to prevent breast cancer recurrence, but patients show variable responses to tamoxifen. Such differential inter-individual response has a significant socioeconomic impact as one in eight women will develop breast cancer and nearly half a million pe...
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American Society for Microbiology
2025-01-01
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| Series: | mBio |
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| Online Access: | https://journals.asm.org/doi/10.1128/mbio.01679-24 |
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| author | Yasmine Alam Sheron Hakopian Lizett Ortiz de Ora Ian Tamburini Julio Avelar-Barragan Sunhee Jung Zane Long Alina Chao Katrine Whiteson Cholsoon Jang Elizabeth Bess |
| author_facet | Yasmine Alam Sheron Hakopian Lizett Ortiz de Ora Ian Tamburini Julio Avelar-Barragan Sunhee Jung Zane Long Alina Chao Katrine Whiteson Cholsoon Jang Elizabeth Bess |
| author_sort | Yasmine Alam |
| collection | DOAJ |
| description | ABSTRACT Tamoxifen is the most prescribed drug used to prevent breast cancer recurrence, but patients show variable responses to tamoxifen. Such differential inter-individual response has a significant socioeconomic impact as one in eight women will develop breast cancer and nearly half a million people in the United States are treated with tamoxifen annually. Tamoxifen is orally delivered and must be activated by metabolizing enzymes in the liver; however, clinical studies show that neither genotype nor hepatic metabolic enzymes are sufficient to predict why some patients have sub-therapeutic levels of the drug. Here, using gnotobiotic- and antibiotics-treated mice, we show that tamoxifen pharmacokinetics are heavily influenced by gut bacteria and prolonged exposure to tamoxifen. Interestingly, 16S rRNA gene sequencing shows tamoxifen does not affect overall microbiota composition and abundance. Metabolomics, however, reveals differential metabolic profiles across the microbiomes of different donors cultured with tamoxifen, suggesting an enzymatic diversity within the gut microbiome that influences response to tamoxifen. Consistent with this notion, we found that β-glucuronidase (GUS) enzymes vary in their hydrolysis activity of glucuronidated tamoxifen metabolites across the gut microbiomes of people. Together, these findings highlight the importance of the gut microbiome in tamoxifen’s pharmacokinetics.IMPORTANCEOne in eight women will develop breast cancer in their lifetime, and tamoxifen is used to suppress breast cancer recurrence, but nearly 50% of patients are not effectively treated with this drug. Given that tamoxifen is orally administered and, thus, reaches the intestine, this variable patient response to the drug is likely related to the gut microbiota composed of trillions of bacteria, which are remarkably different among individuals. This study aims to understand the impact of the gut microbiome on tamoxifen absorption, metabolism, and recycling. The significance of our research is in defining the role that gut microbes play in tamoxifen pharmacokinetics, thus paving the way for more tailored and effective therapeutic interventions in the prevention of breast cancer recurrence. |
| format | Article |
| id | doaj-art-7903dcdc4fe74e8d87356ce114dafe73 |
| institution | Kabale University |
| issn | 2150-7511 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | mBio |
| spelling | doaj-art-7903dcdc4fe74e8d87356ce114dafe732025-01-08T14:00:38ZengAmerican Society for MicrobiologymBio2150-75112025-01-0116110.1128/mbio.01679-24Variation in human gut microbiota impacts tamoxifen pharmacokineticsYasmine Alam0Sheron Hakopian1Lizett Ortiz de Ora2Ian Tamburini3Julio Avelar-Barragan4Sunhee Jung5Zane Long6Alina Chao7Katrine Whiteson8Cholsoon Jang9Elizabeth Bess10Department of Biological Chemistry, University of California Irvine, Irvine, California, USADepartment of Pharmaceutical Sciences, University of California Irvine, Irvine, California, USADepartment of Chemistry, University of California Irvine, Irvine, California, USADepartment of Biological Chemistry, University of California Irvine, Irvine, California, USADepartment of Molecular Biology & Biochemistry, University of California Irvine, Irvine, California, USADepartment of Biological Chemistry, University of California Irvine, Irvine, California, USADepartment of Chemistry, University of California Irvine, Irvine, California, USADepartment of Biological Chemistry, University of California Irvine, Irvine, California, USADepartment of Molecular Biology & Biochemistry, University of California Irvine, Irvine, California, USADepartment of Biological Chemistry, University of California Irvine, Irvine, California, USADepartment of Chemistry, University of California Irvine, Irvine, California, USAABSTRACT Tamoxifen is the most prescribed drug used to prevent breast cancer recurrence, but patients show variable responses to tamoxifen. Such differential inter-individual response has a significant socioeconomic impact as one in eight women will develop breast cancer and nearly half a million people in the United States are treated with tamoxifen annually. Tamoxifen is orally delivered and must be activated by metabolizing enzymes in the liver; however, clinical studies show that neither genotype nor hepatic metabolic enzymes are sufficient to predict why some patients have sub-therapeutic levels of the drug. Here, using gnotobiotic- and antibiotics-treated mice, we show that tamoxifen pharmacokinetics are heavily influenced by gut bacteria and prolonged exposure to tamoxifen. Interestingly, 16S rRNA gene sequencing shows tamoxifen does not affect overall microbiota composition and abundance. Metabolomics, however, reveals differential metabolic profiles across the microbiomes of different donors cultured with tamoxifen, suggesting an enzymatic diversity within the gut microbiome that influences response to tamoxifen. Consistent with this notion, we found that β-glucuronidase (GUS) enzymes vary in their hydrolysis activity of glucuronidated tamoxifen metabolites across the gut microbiomes of people. Together, these findings highlight the importance of the gut microbiome in tamoxifen’s pharmacokinetics.IMPORTANCEOne in eight women will develop breast cancer in their lifetime, and tamoxifen is used to suppress breast cancer recurrence, but nearly 50% of patients are not effectively treated with this drug. Given that tamoxifen is orally administered and, thus, reaches the intestine, this variable patient response to the drug is likely related to the gut microbiota composed of trillions of bacteria, which are remarkably different among individuals. This study aims to understand the impact of the gut microbiome on tamoxifen absorption, metabolism, and recycling. The significance of our research is in defining the role that gut microbes play in tamoxifen pharmacokinetics, thus paving the way for more tailored and effective therapeutic interventions in the prevention of breast cancer recurrence.https://journals.asm.org/doi/10.1128/mbio.01679-24human gut microbiometamoxifenbreast cancer |
| spellingShingle | Yasmine Alam Sheron Hakopian Lizett Ortiz de Ora Ian Tamburini Julio Avelar-Barragan Sunhee Jung Zane Long Alina Chao Katrine Whiteson Cholsoon Jang Elizabeth Bess Variation in human gut microbiota impacts tamoxifen pharmacokinetics mBio human gut microbiome tamoxifen breast cancer |
| title | Variation in human gut microbiota impacts tamoxifen pharmacokinetics |
| title_full | Variation in human gut microbiota impacts tamoxifen pharmacokinetics |
| title_fullStr | Variation in human gut microbiota impacts tamoxifen pharmacokinetics |
| title_full_unstemmed | Variation in human gut microbiota impacts tamoxifen pharmacokinetics |
| title_short | Variation in human gut microbiota impacts tamoxifen pharmacokinetics |
| title_sort | variation in human gut microbiota impacts tamoxifen pharmacokinetics |
| topic | human gut microbiome tamoxifen breast cancer |
| url | https://journals.asm.org/doi/10.1128/mbio.01679-24 |
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