Journal article
Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases
Drug metabolism and disposition, Vol.35(11), pp.2006-2014
11/2007
Handle:
https://hdl.handle.net/2376/115194
PMID: 17664247
Abstract
Tamoxifen (TAM) is an antiestrogen that has been widely used in the treatment and prevention of breast cancer in women. One of the major mechanisms of metabolism and elimination of TAM and its major active metabolites 4-hydroxytamoxifen (4-OH-TAM) and 4-OH-N-desmethyl-TAM (endoxifen; 4-hydroxy-N-desmethyl-tamoxifen) is via glucuronidation. Although limited studies have been performed characterizing the glucuronidation of 4-OH-TAM, no studies have been performed on endoxifen. In the present study, characterization of the glucuronidating activities of human UDP glucuronosyltransferases (UGTs) against isomers of 4-OH-TAM and endoxifen was performed. Using homogenates of individual UGT-overexpressing cell lines, UGTs 2B7 approximately 1A8 > UGT1A10 exhibited the highest overall O-glucuronidating activity against trans-4-OH-TAM as determined by Vmax/K(M), with the hepatic enzyme UGT2B7 exhibiting the highest binding affinity and lowest K(M) (3.7 microM). As determined by Vmax/K(M), UGT1A10 exhibited the highest overall O-glucuronidating activity against cis-4-OH-TAM, 10-fold higher than the next-most active UGTs 1A1 and 2B7, but with UGT1A7 exhibiting the lowest K(M). Although both N- and O-glucuronidation occurred for 4-OH-TAM in human liver microsomes, only O-glucuronidating activity was observed for endoxifen; no endoxifen-N-glucuronidation was observed for any UGT tested. UGTs 1A10 approximately 1A8 > UGT2B7 exhibited the highest overall glucuronidating activities as determined by Vmax/K(M) for trans-endoxifen, with the extrahepatic enzyme UGT1A10 exhibiting the highest binding affinity and lowest K(M) (39.9 microM). Similar to that observed for cis-4-OH-TAM, UGT1A10 also exhibited the highest activity for cis-endoxifen. These data suggest that several UGTs, including UGTs 1A10, 2B7, and 1A8 play an important role in the metabolism of 4-OH-TAM and endoxifen.
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Details
- Title
- Glucuronidation of active tamoxifen metabolites by the human UDP glucuronosyltransferases
- Creators
- Dongxiao Sun - Cancer Prevention and Control, Penn State Cancer Institute, Department of Pharmacology, Penn State University College of Medicine, Hershey, PA 17033, USAArun K SharmaRyan W DellingerAndrea S Blevins-PrimeauRenee M BallietGang ChenTelih BoyiriShantu AminPhilip Lazarus
- Publication Details
- Drug metabolism and disposition, Vol.35(11), pp.2006-2014
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- United States
- Grant note
- P01 CA068384 / NCI NIH HHS R01 DE013158 / NIDCR NIH HHS P01-68384 / PHS HHS
- Identifiers
- 99900548268901842
- Language
- English
- Resource Type
- Journal article