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Tamoxifen Metabolism and CYP2D6 - How Genes and Antidepressants Prevent Benefits


Updated September 23, 2011

Written or reviewed by a board-certified physician. See About.com's Medical Review Board.

Tamoxifen, Zoloft, Effexor

Tamoxifen, Zoloft, Effexor

Photo © Pam Stephan

Tamoxifen Transformation:

After you've had treatment for estrogen-sensitive breast cancer, your oncologist may prescribe tamoxifen. To help prevent a recurrence, a standard course is one pill daily for five years after primary treatments. When you take tamoxifen, your liver can transform it into endoxifen, a very powerful estrogen blocker. If the endoxifen is successfully produced, it fits into the estrogen receptors of breast cancer cells, preventing or slowing the growth of those cells. Certain drugs or a genetic resistance can inhibit that important transformation, cancelling out the benefits of tamoxifen.

How Your Body Uses Tamoxifen:

Once you take a tamoxifen tablet, your liver uses the CYP2D6 enzyme to metabolize it and convert it into endoxifen. This chemical - endoxifen - is the real workhorse when it comes to blocking estrogen receptors in breast tissue. Endoxifen fits into the estrogen receptors of hormone-sensitive cells and prevents natural estrogen from getting into those cells. That blocking action takes place only if your body successfully converts tamoxifen into endoxifen - but this process may be prevented by certain antidepressants or by a variation of the CYP2D6 gene.

Importance of the CYP2D6 Enzyme:

Anytime you take a drug, your body needs to metabolize it - break it down into active chemicals that are used in important health processes. Your liver uses special enzymes like cytochrome P2D6 to convert many common drugs for use by your body. Since we all have unique combinations of genetic instructions, we metabolize drugs differently. If you don't metabolize tamoxifen well - whether that is due to other drugs you take or genes you have - it won't give you the full anti-estrogen benefit.

Tamoxifen Resistance and the CYP2D6 Gene:

Some of us (between 7% and 10% of breast cancer patients) are genetically resistant to the benefits of tamoxifen. This can be caused by a variation of the CYP2D6 gene. This gene makes the critical enzyme that converts tamoxifen to endoxifen. If your body metabolizes tamoxifen very slowly or not at all, you may be at a higher risk for recurrence of breast cancer. But you can be tested for tamoxifen resistance and use a different class of drugs - aromatase inhibitors - to prevent the production of estrogen. Aromatase inhibitors are prescribed for postmenopausal women.

Antidepressants May Prevent Benefits of Tamoxifen:

Tamoxifen has a variety of side effects - it can produce menopausal sensations such as hot flashes, osteoporosis and vaginal dryness. Many women take an antidepressant to counteract these symptoms, but if that drug is an SSRI (selective serotonin reuptake inhibitor) such as Paxil or Zoloft, the benefits of tamoxifen may be cancelled out. An antidepressant that is also an SSRI prevents the CYP2D6 enzyme from properly converting Tamoxifen into endoxifen. Discuss your antidepressant choices with your oncologist to make sure that all the drugs you are taking are working well together.


CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. Jin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, Skaar T, Storniolo AM, Li L, Araba A, Blanchard R, Nguyen A, Ullmer L, Hayden J, Lemler S, Weinshilboum RM, Rae JM, Hayes DF, Flockhart DA. J Natl Cancer Inst. 2005 Jan 5;97(1):30-9.

Drug Interactions and Pharmacogenomics in the Treatment of Breast Cancer and Depression. N. Lynn Henry, M.D., Ph.D., Vered Stearns, M.D., David A. Flockhart, M.D., Ph.D., Daniel F. Hayes, M.D., and Michelle Riba, M.D. Am J Psychiatry 165:1251-1255, October 2008.

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