Tamoxifen Metabolism and CYP2D6 Overview of the Action of CYP2D6
- Author: Maurie Markman, MD; Chief Editor: Bruce Buehler, MD more...
Overview of the Action of CYP2D6
Since the early 1980s, adjuvant therapy with tamoxifen has been the standard approach to reducing risk of recurrence in women with estrogen receptor (ER)–positive breast cancer. Long-term data have demonstrated that the use of tamoxifen reduces recurrence and mortality by more than 30%.[1] Aromatase inhibitors (AIs), such as anastrozole (Arimidex) and letrozole (Femara), have been proven to be as effective as or superior to tamoxifen, but because of differing adverse-effect profiles and cost, tamoxifen remains the treatment of choice for a large percentage of women.
Tamoxifen is metabolized via CYP2D6 into endoxifen (4-OH-N-desmethyl-tamoxifen), its primary active metabolite. Multiple investigations have identified genetic variants of CYP2D6 that can affect its activity, which in turn affects the metabolism of tamoxifen.
The proficiency with which CYP2D6 metabolizes tamoxifen was assumed to be associated with the specific variant of the gene that an individual possesses, on the basis of studies that were conducted in breast cancer patients taking selective serotonin reuptake inhibitors (SSRIs) to relieve hot flashes.[2, 3, 4]
Specifically, because SSRIs inhibit CYP2D6, significantly lower endoxifen concentrations were also found in the studies’ patients. Further analysis identified 3 different groups of patients, based on genetic variants of CYP2D6: patients with 2 wild-type (wt), or normal, alleles; those with 1 non-wt allele; and those with 2 non-wt alleles. In a direct dose-gene effect, patients with 2 non-wt alleles had lower concentrations of endoxifen than did those with 1 non-wt allele, and patients with 2 wt alleles had endoxifen levels similar to those of poor metabolizers of tamoxifen who were not taking SSRIs.[3, 4]
Follow-up studies identified the *4 variant (1846G>A) as the most common allele associated with poor metabolism of tamoxifen.[5, 6] It is estimated that 7-10% of whites are poor metabolizers of tamoxifen based on specific CYP2D6 alleles.[7]
For more information, see Breast Cancer.
Tamoxifen is metabolized via CYP2D6 into endoxifen (4-OH-N-desmethyl-tamoxifen), its primary active metabolite. Multiple investigations have identified genetic variants of CYP2D6 that can affect its activity, which in turn affects the metabolism of tamoxifen.
The proficiency with which CYP2D6 metabolizes tamoxifen was assumed to be associated with the specific variant of the gene that an individual possesses, on the basis of studies that were conducted in breast cancer patients taking selective serotonin reuptake inhibitors (SSRIs) to relieve hot flashes.[2, 3, 4]
Specifically, because SSRIs inhibit CYP2D6, significantly lower endoxifen concentrations were also found in the studies’ patients. Further analysis identified 3 different groups of patients, based on genetic variants of CYP2D6: patients with 2 wild-type (wt), or normal, alleles; those with 1 non-wt allele; and those with 2 non-wt alleles. In a direct dose-gene effect, patients with 2 non-wt alleles had lower concentrations of endoxifen than did those with 1 non-wt allele, and patients with 2 wt alleles had endoxifen levels similar to those of poor metabolizers of tamoxifen who were not taking SSRIs.[3, 4]
Follow-up studies identified the *4 variant (1846G>A) as the most common allele associated with poor metabolism of tamoxifen.[5, 6] It is estimated that 7-10% of whites are poor metabolizers of tamoxifen based on specific CYP2D6 alleles.[7]
For more information, see Breast Cancer.
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