Annals of Oncology Advance Access published online on October 18, 2007
Annals of Oncology, doi:10.1093/annonc/mdm434
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© 2007 European Society for Medical Oncology
Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism
1 The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen
2 Section for Endocrinology, Institute of Medicine, University of Bergen, N-5021 Bergen
3 Dr E. Martens Research Group for Biological Psychiatry, Department of Clinical Medicine, University of Bergen, N-5021 Bergen
4 Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, N-5021 Bergen
5 Cancer Clinic, St Olavs University Hospital, N-7006 Trondheim
6 Department of Cancer Research and Molecular Medicine, Trondheim University Hospital, Norwegian University of Science and Technology, N-7006 Trondheim
7 Department of Surgery, Haukeland University Hospital, N-5021 Bergen, Norway
* Correspondence to: Dr E. A. Lien, Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen, Norway. Tel: +47-55-97-43-71; Fax: +47-55-97-58-14; E-mail: ernst.lien{at}med.uib.no
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Abstract |
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 Top Abstract introductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Background: Tamoxifen is hydroxylated by cytochrome P450 (CYP) 2D6 to the potent metabolites 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam), which are both conjugated by sulphotransferase (SULT)1A1. Clinical studies indicate that CYP2D6 and SULT1A1 genotypes are predictors for treatment response to tamoxifen. Therefore, we examined the relationship between CYP2D6 genotype, SULT1A1 genotype, SULT1A1 copy number and the pharmacokinetics of tamoxifen.
Patients and methods: The serum levels of tamoxifen and metabolites of 151 breast cancer patients were measured by high-pressure liquid chromatography–tandem mass spectrometry. The CYP2D6 and SULT1A1 polymorphisms and SULT1A1 copy number were determined by long PCR, PCR-based restriction fragment length polymorphism, DNA sequencing and fluorescence-based PCR.
Results: The levels of 4OHtam, 4OHNDtam and N-demethyltamoxifen were associated with CYP2D6 predicted enzymatic activity (P < 0.05). The SULT1A1 genotype or copy number did not influence the levels of tamoxifen and its metabolites. However, the ratios of N-demethyltamoxifen/tamoxifen and N-dedimethyltamoxifen/N-demethyltamoxifen were related to SULT1A1 genotype.
Conclusion: CYP2D6 and SULT1A1 genotypes may partly explain the wide inter-individual variations in the serum levels of tamoxifen and its metabolites. We propose that therapeutic drug monitoring should be included in studies linking CYP2D6 and SULT1A1 genotypes to clinical outcome.
breast cancer, CYP2D6, endoxifen, 4-OH-N-demethyltamoxifen, SULT1A1, tamoxifen
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Tamoxifen metabolism shows considerable inter-individual variation. The bioconversion of tamoxifen involves N-oxidation, N-demethylation and hydroxylation (Figure 1A). The cytochrome (CYP)2D6 enzyme demethylates tamoxifen [1] and hydroxylates tamoxifen and N-demethyltamoxifen (NDtam) to the clinically potent metabolites 4-hydroxytamoxifen (4OHtam) and 4-hydroxy-N-demethyltamoxifen (4OHNDtam, endoxifen) [2, 3]. Tamoxifen is further inactivated by sulphotransferase (SULT) 1A1, UDP-glucuronosyltransferase (UGT) 2B15 and UGT1A4 [4, 5].
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The CYP2D6 and SULT1A1 genotypes generate different subgroups in the population on the basis of altered enzymatic activity caused by genetic polymorphisms [4, 6–8]. Another factor that may also affect enzymatic activity is gene deletion and duplication. Recently, Hebbring et al. [9] observed that SULT1A1 enzymatic activity is also correlated with SULT1A1 gene copy numbers in vitro. Results from recent studies indicate that CYP2D6 and SULT1A1 genotypes may influence outcome of tamoxifen-treated patients [10–13]. However, some of these studies, which lack the intermediary step of monitoring the serum concentrations of tamoxifen and its metabolites, report different results regarding CYP2D6 [12, 13]. In the present study, we examined the influence of CYP2D6 and SULT1A1 genotypes and SULT1A1 copy number on the pharmacokinetics of tamoxifen during steady-state treatment of 151 breast cancer patients. Our results indicate that the CYP2D6 and SULT1A1 genotypes influence the pharmacokinetics of tamoxifen, whereas SULT1A1 copy number does not.
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patients and methods |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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study population
From October 2002 to October 2003, Caucasian women with breast cancer were consecutively recruited from Haukeland University Hospital, St Olav University Hospital and Førde Central Hospital in Norway. All patients were oestrogen receptor and/or progesterone receptor positive. The median (range) age of the patients was 57 (32–85). Written informed consent was provided by each patient. Due to the long half-life of tamoxifen, only patients adjuvantly treated with 20 mg tamoxifen per day for at least 80 days were included in the study in order to ensure that patients had reached steady-state drug levels [14, 15].
determination of tamoxifen and its metabolites concentrations
We used a high-pressure liquid chromatography–tandem mass spectrometry system that was developed for the determination of tamoxifen and its metabolites in serum [16]. The assay was modified to improve the sensitivity by changing the API 2000/Qtrap mass spectrometry system from Applied Biosystems (AB MDS Sciex, Concord, Canada) to the API 4000, equipped with TurboIonSpray.
CYPD6 genotyping
The most common CYP2D6 PM-associated alleles (*3, *4, *5 and *6) and the ultra rapid metaboliser (UM)-associated CYP2D6 gene duplication (*2 x 2) were tested to identify >97% of CYP2D6 poor metabolisers [17, 18] and 
20% of subjects with ultra rapid CYP2D6 enzyme activity [6].
CYP2D6 alleles that tested negative for all the variants were classified as CYP2D6*1. For detection of the CYP2D6*3 and CYP2D6*4 polymorphisms, the entire CYP2D6 gene (4.7 kb) was amplified by long PCR using the CYP2D6-specific primers CYP-P2 5'-GAAGGCTTTGCAGGCTTCAGGA-3' and CYP-N 5'-GCCTCAACGTACCCCTGTCTC-3'. The resulting PCR product was used as a template in two separate PCR-restriction fragment length polymorphism (RFLP) assays. The primers CYP-407A 5'-GACCCAGCTGGATGAGCTGCTAACTGAGCCC-3' and CYP-408A 5'-CCCAAATGACCTCCAATTCTGCACCTGTC-3' were used for the CYP2D6*3 assay and CYP-5B 5'-CGAGCAGAGGCGCTTCTC-3' and CYP-6B 5'-GCGAGGGTCGTCGTACTC-3' for CYP2D6*4. The CYP2D6*3 assay was carried out by using MspI (New England Biolabs) digestion while CYP2D6*4 assay by using BstNI (New England Biolabs). The absence or presence of the CYP2D6*3 and CYP2D6*4 alleles were scored according to the patterns of restriction fragments upon agarose gel electrophoresis.
Genotyping for the CYP2D6*6 allele was carried out by a predeveloped allele-specific 5' nuclease assay with TaqMan probes (Applied Biosystems) and allele discrimination was carried out using the ABI Prism 7700 sequence detection system (Applied Biosystems), according to the manufacturer's instructions.
The CYP2D6*5 gene deletion allele was identified by a slightly modified long PCR assay as described by Steen et al. [19] and UM-associated CYP2D6 gene duplication (*2 x 2) was determined by long PCR [20].
SULT1A1 genotyping
The SULT1A1*2 variant allele was primarily determined by a hybridisation probe-based real time PCR assay, using the primer 5'-GGGTCTCTAGGAGAGGTGGC-3' (forward) and 5'-GCTGTGGTCCATGAACTCCT-3' (reverse) as described by Tang et al. [21]. This resulted in misclassification and underreporting of the variant SULT1A1*2 allele due to mismatches in the forward primer sequence. We therefore used another primer pair [5'-GGTTGAGGAGTTGGCTCTGC-3' (forward) and 5'-ATGAACTCCTGGGGGACGGT-3' (reverse)] for this assay [10, 22]. The detection probe used was 5'-LC Red640-CAGGGAGCGCCCCACAA-PH and the anchor probe was 5'-GAACCATGAAGTCCACGGTCTCCTCT-FL (TIB MOLBIOL, Germany).
To verify the results, a PCR-based RFLP assay was carried out [10, 22] and the resulting PCR product was exposed to restriction endonuclease HaeII (New England BioLabs). In addition, the PCR product was bidirectionally sequenced using Big Dye Terminator version 3.1 Cycle Sequencing kit according to the manufacturer's recommendations on an ABI Prism 3700 DNA Analyzer (Applied Biosystems).
SULT1A1 gene copy number
The SULT1A1 copy number was estimated by calculating the height and area ratio of 210 bp amplicon of SULT1A1 to the reference 205 bp amplicon of SULT1A2 as described by Hebbring et al. [9]. A set of PCR primers 5'-GGGTCTCTAGGAGAGGTGGC-3' (forward) and 5'-GCTGTGGTCCATGAACTCCT-3' (reverse) were used to coamplify the 210-bp fragment within exon 2 and exon 3 of SULT1A1 and a 205-bp fragment within exon 3 and exon 4 of SULT1A2. The PCR products were analysed on ABI3100 DNA analyzer (Applied Biosystems).
statistical analysis
The CYP2D6 genotypes were subdivided into four groups and ranked according to their predicted increasing enzymatic activity: PM [subjects with any combination of two nonfunctional variant type (Vt) alleles], wild type (Wt)/Vt extensive metaboliser (EM), Wt/Wt EM and UM (heterozygous Vt allele *2 x 2). The SULT1A1 genotypes and gene dosage were also subdivided into groups and ranked according to their predicted increasing enzymatic activity: *2/*2, *1/*2 and *1/*1 and increasing copy number, respectively. Mean values (95% confidence interval) are given for Gaussian-distributed variables and median values (range) for variables showing skewed distributions. The serum levels of tamoxifen, 4OHtam, 4OHNDtam, NDtam, NDDtam and tamoxifen-N-oxide (tamNox) levels were log transformed to normalise their distribution. Logistic regression analysis was used to assess whether CYP2D6 and SULT1A1 genotypes and SULT1A1 copy number influence serum concentrations of tamoxifen and its metabolites after adjustment for age. All analyses were conducted with the SPSS statistical package (version 12; SPSS). All statistical tests were two sided.
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results |
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The observed distribution of the CYP2D6 PM-, Wt/Vt EM-, Wt/Wt EM- and UM- genotypes and allele frequencies of CYP2D6*1, *3, *4, *5, *6 and *2 x 2 are shown in Table 1. The overall CYP2D6 genotype distribution was in accordance with an expected Hardy–Weinberg equilibrium. As for SULT1A1, the distribution of the SULT1A1*1/*1, SULT1A1*1/*2 and SULT1A1*2/*2 genotypes and the allele frequencies of SULT1A1*1 and SULT1A1*2 are shown in Table 1 and were not in Hardy–Weinberg equilibrium. The results were verified by a PCR-based RFLP assay and bidirectional DNA sequencing. The frequency of SULT1A1 copy number was also determined among the 151 Caucasian patients (Table 1).
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The concentrations values measured are minimum levels at steady state (Css,min). The median (range) serum concentration of tamoxifen, 4OHtam, 4OHNDtam, NDtam, NDDtam and tamNox were 90 (27–302) ng/ml, 5.7 (1.7–17.2) ng/ml, 49.4 (24.3–184.8) ng/ml, 226 (90–691) ng/ml, 37.0 (11.4–93.4) ng/ml and 9.4 (2.7–37.9) ng/ml, respectively. The range of the serum levels of tamoxifen indicates that all patients complied with the tamoxifen administration regimen.
The CYP2D6 predicted enzymatic activity increased with decreasing serum levels of NDtam, while the serum levels of 4OHtam and 4OHNDtam increased (Table 2). The metabolic ratios of 4OHtam to tamoxifen, 4OHNDtam to NDtam and NDDtam to NDtam were markedly affected by the CYP2D6 genotype in a manner consistent with a gene-dose effect (Figure 1B), whereas the ratios of NDtam to tamoxifen were inversely related to the predicted increasing enzymatic activity of CYP2D6 genotype (Figure 1B).
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The SULT1A1 genotype or copy number did not significantly affect the levels of tamoxifen and its metabolites (Table 2). The serum metabolic ratios of 4OHtam to tamoxifen, 4OHNDtam to NDtam and tamNox to tamoxifen were not associated with SULT1A1 predicted enzymatic activity (data not shown). However, the serum concentration ratios of NDtam to tamoxifen were positively associated with SULT1A1*2/*2, SULT1A1*1/*2 and SULT1A1*1/*1 (Figure 1B). The opposite was observed for the concentration ratios of NDDtam to NDtam (Figure 1B).
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Recent studies link genetic polymorphisms of tamoxifen-metabolising enzymes to clinical outcome [10–13]. However, some of these studies, which report different results [12, 13], lack the intermediary step of monitoring the serum concentrations of tamoxifen and its metabolites. In the present study, we examined the relationship between CYP2D6 and SULT1A1 polymorphisms and serum concentrations of tamoxifen and its metabolites.
4OHNDtam is considered to be the predominant active metabolite of tamoxifen as its pharmacological potency is equivalent to that of 4OHtam and its concentration in blood and tissues is several fold that of 4OHtam [14, 23]. Results from in vitro studies indicate that the major metabolic route of 4OHNDtam is from NDtam [3]. This conversion is catalysed by CYP2D6 [1–3]. We observed significant associations between the genotype-mediated variation of CYP2D6 activity and serum concentrations of 4OHtam, 4OHNDtam, NDtam and the metabolic ratios of 4OHNDtam to NDtam and NDtam to NDDtam. These were markedly affected by the CYP2D6 genotype in a manner consistent with a gene-dose effect. In line with this, serum levels of NDtam and the ratios of NDtam to tamoxifen were inversely related to CYP2D6 activity. This study demonstrates the influence of CYP2D6 genotype on the hydroxylation of tamoxifen to 4OHtam and demethylation of NDtam to NDDtam in vivo, as earlier described in in vitro studies [1–3].
We did not find any significant associations between SULT1A1 genotypes and serum levels of 4OHtam or 4OHNDtam. This may be due to the fact that these metabolites are not only conjugated by SULT1A1 but also by UGTs [4, 5, 23] which represent an alternative pathway that may compensate for low sulphation activity. We observed, however, associations between the metabolic ratios of tamoxifen and its demethylated metabolites and the predicted activity of SULT1A1 genotypes. On the other hand, no association was observed between the SULT1A1 copy numbers and the pharmacokinetics of tamoxifen.
In our study population, the SULT1A1 genotype was not in Hardy–Weinberg equilibrium as earlier observed [7, 8]. This may be due to the sample size, genotyping errors or biological selection effects. Methodological errors can be excluded since our SULT1A1 results were determined by three different assays. A skewed distribution, by chance due to a limited number of patients in the study population is thus most likely.
A limitation of the present study is the lack of information about concomitant medication of the patients included. Tamoxifen-treated patients often use several additional drugs [14, 24, 25]. We have observed in a previous study that included 111 breast cancer patients, where two-thirds used other drugs and one-third used a total of 37 different medications that are known to interact with tamoxifen-metabolising enzymes. This illustrates the complexity in evaluating the influence of concomitant medication during tamoxifen treatment. Hot flushes, which are a frequently observed side-effect of tamoxifen, are treated with selective serotonin reuptake inhibitors, such as paroxetine and fluoxetine in United States, that are known to inhibit CYP2D6 and influence tamoxifen metabolism [25, 26]. However, it should be noted that these drugs are not approved in Norway for the treatment of hot flushes.
In conclusion, CYP2D6 genotype influences conversion of tamoxifen to potent hydroxylated metabolites in a manner consistent with a gene-dose effect. Patients carrying CYP2D6 alleles with high-predicted enzymatic activity have high serum levels of 4OHtam and 4OHNDtam. The SULT1A1 genotype or copy number did not significantly affect the levels of tamoxifen and its metabolites. However, associations were observed between the SULT1A1 genotype and the metabolic ratios of tamoxifen and its demethylated metabolites. Our observations indicate that the CYP2D6 and SULT1A1 genotype distribution may partly explain the wide inter-individual variations in the pharmacokinetics of tamoxifen. As several additional drugs and enzymes may also influence tamoxifen metabolism, we propose that therapeutic drug monitoring should be included in tamoxifen trials that evaluate the effects of CYP2D6 and SULT1A1 genotype on treatment outcome.
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funding |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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Norwegian Cancer Society, The Research Council of Norway, Dr Einar Martens Foundation, Grieg Foundation and Frank Mohn Foundation.
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Acknowledgements |
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TopAbstractintroductionpatients and methodsresultsdiscussionfundingAcknowledgementsReferences |
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We thank Dr Geirfinn Vagstad for help with providing the serum samples from Førde Central Hospital, and Carol Cook for proof-reading the manuscript.
Received for publication July 5, 2007. Accepted for publication July 26, 2007.
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References |
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