Effects of CYP2D6 and SULT1A1 genotypes including SULT1A1 gene copy number on tamoxifen metabolism.
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.


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.


CONCLUSIONS
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.
Gjerde
J
J
The Hormone Laboratory, Haukeland University Hospital, N-5021 Bergen.
Hauglid
M
M
Breilid
H
H
Lundgren
S
S
Varhaug
J E
JE
Kisanga
E R
ER
Mellgren
G
G
Steen
V M
VM
Lien
E A
EA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000493:pharmacokinetics*; D015239:Arylsulfotransferase / Q000235:genetics* / Q000378:metabolism; D001711:Biotransformation / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018628:Gene Dosage; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009664:Norway; D012150:Polymorphism, Restriction Fragment Length; D020845:Selective Estrogen Receptor Modulators / Q000493:pharmacokinetics*; D013629:Tamoxifen / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*
D018931:Antineoplastic Agents, Hormonal; D020845:Selective Estrogen Receptor Modulators; D013629:Tamoxifen; C016601:afimoxifene; C055492:4-hydroxy-N-desmethyltamoxifen; D019389:Cytochrome P-450 CYP2D6; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human