title: Polymorphisms in cytochrome P4503A5 (CYP3A5) may be associated with race and tumor characteristics, but not metabolism and side effects of tamoxifen in breast cancer patients.
abstract: Tamoxifen (TAM) is widely used for treatment and prevention of breast cancer. TAM is metabolized by cytochrome P450 (CYP450) enzymes, including CYP3A5. Although two genetic polymorphisms in CYP3A5 are known (CYP3A5*3 and CYP3A5*6), the effects of these polymorphisms on TAM metabolism, TAM side effects, and tumor characteristics are unknown. Thus, this work tested the hypothesis that CYP3A5 polymorphisms are associated with differential TAM levels, TAM side effects, and tumor characteristics in breast cancer patients. Postmenopausal women with breast cancer (n=98) were recruited from a single cancer center. Polymorphic status was established using polymerase chain reactions (PCR). The associations between polymorphic status, race, TAM levels, side effects, and tumor characteristics were assessed using t-tests and logistic regression models. The data indicate that 40.7% of the breast cancer patients had the CYP3A5*3 polymorphism, and 9.1% had the CYP3A5*6 polymorphism. In addition, Caucasian women were 26 times more likely to carry the CYP3A5*3 polymorphism than African American (AA) women, whereas AA women were nine times more likely to carry the CYP3A5*6 polymorphism than Caucasian women. No significant differences were seen in TAM or TAM metabolite levels or TAM side effects by polymorphic status. There was a significant difference, however, in mean tumor size in women with the CYP3A5*6 polymorphism (3.6+/-0.98 cm) compared to those without the polymorphism (2.0+/-0.18 cm) (P<0.02). Taken together, these data suggest that racial differences in CYP3A5 polymorphisms exist although the polymorphisms do not appear to be associated with levels of TAM metabolites and side effects.
authors.affiliation: Department of Epidemiology and Preventive Medicine, School of Medicine, University of Maryland, 600 West Redwood Street, Howard Hall Room 133, Baltimore, MD 21201, USA.
authors.forename: April N
authors.initials: AN
authors.lastname: Tucker
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Tkaczuk
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Lewis
authors.forename: Dragana
authors.initials: D
authors.lastname: Tomic
authors.forename: Chang K
authors.initials: CK
authors.lastname: Lim
authors.forename: Jodi A
authors.initials: JA
authors.lastname: Flaws
mesh_terms: D000328:Adult; D001741:Black or African American; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000453:epidemiology* / Q000235:genetics*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D006801:Humans; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017698:Postmenopause; D013629:Tamoxifen / Q000009:adverse effects* / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism*; D044465:White People
chemical_list: D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; C016601:afimoxifene; D003577:Cytochrome P-450 Enzyme System; C104464:CYP3A protein, human; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A