title: Effect of MRP2 and MRP3 Polymorphisms on Anastrozole Glucuronidation and MRP2 and MRP3 Gene Expression in Normal Liver Samples.
abstract: Anastrozole is an aromatase inhibitor (AI) used as adjuvant therapy for breast cancer. Anastrozole is subject to direct glucuronidation catalyzed by UDP-glucuronosyltransferase1A4 (UGT1A4). Interindividual variability in anastrozole glucuronidation may be affected by UGT1A4 SNPs. Interplay between drug metabolizing genes such as UGT1A4 and transporter genes may also be affected by genetic variability. Thus, we hypothesize that genetic variability in MRPs could influence anastrozole glucuronidation. The correlation between UGT1A4 and MRP2 or MRP3 transporter gene expressions and the correlation between MRP2 or MRP3 mRNA and anastrozole glucuronidation were analyzed in normal human liver samples. MRP2 and MRP3 mRNA levels were significantly correlated with UGT1A4 mRNA, with anastrozole glucuronidation and with each other (p<0.05). The data also demonstrated thatMRP2SNPs are positively correlated with MRP2 mRNA expression, while there was no association betweenMRP3SNPs from this study and MRP3 expression. Significant correlations (p<0.05) between certainMRP2SNPs (3972C>T, 2366C>T and -24C>T) and anastrozole glucuronidation were observed. There were no observed correlations between MRP3 SNPs and anastrozole glucuronidation. MRP2 polymorphisms have been identified as playing a role in the disposition of other drugs, and the data presented here indicate for the first time thatMRP2SNPs could influence anastrozole metabolism and contribute to interindividual variation in treatment responses.
authors.affiliation: Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Vineetha Koroth
authors.initials: VK
authors.lastname: Edavana
authors.affiliation: Department of Environmental and Occupational Health, College of Public Health, Little Rock, USA.
authors.forename: Rosalind B
authors.initials: RB
authors.lastname: Penney
authors.affiliation: Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Aiwei
authors.initials: A
authors.lastname: Yao-Borengasser
authors.affiliation: Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Athena
authors.initials: A
authors.lastname: Starlard-Davenport
authors.affiliation: Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Ishwori B
authors.initials: IB
authors.lastname: Dhakal
authors.affiliation: Division of Medical Genetics, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Kadlubar
keywords: Anastrozole Glucuronidation; MRP2 Polymorphisms; MRP2 gene expression; MRP3 Polymorphisms; MRP3 gene expression