Journal article
Characterization of raloxifene glucuronidation. Potential role of UGT1A8 genotype on raloxifene metabolism in vivo
Cancer prevention research (Philadelphia, Pa.), Vol.6(7), pp.719-730
07/2013
Handle:
https://hdl.handle.net/2376/105291
PMCID: PMC4057281
PMID: 23682072
Abstract
Raloxifene is a 2
nd
-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4′-glucuronide (ral-4′-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation
in vivo
. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (
p
trend
=0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed
in vitro
with cell line over-expressing UGT1A8 variants, the UGT1A8*2 variant was significantly (
p=
0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4′-Gluc exhibited 1/100
th
the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised ∼99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4′-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (
p
trend
=0.0025), ral-4′-Gluc (
p
trend
=0.001), and total raloxifene glucuronides (
p
trend
=0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] vs intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] vs fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene.
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Details
- Title
- Characterization of raloxifene glucuronidation. Potential role of UGT1A8 genotype on raloxifene metabolism in vivo
- Creators
- Dongxiao Sun - Department of Pharmacology, Pennsylvania State College of Medicine, 500 University Dr. Hershey, PA, 17033, USANathan R Jones - Department of Pharmacology, Pennsylvania State College of Medicine, 500 University Dr. Hershey, PA, 17033, USAAndrea Manni - Department of Medicine, Pennsylvania State College of Medicine, 500 University Dr. Hershey, PA, 17033, USAPhilip Lazarus - Department of Pharmacology, Pennsylvania State College of Medicine, 500 University Dr. Hershey, PA, 17033, USA
- Publication Details
- Cancer prevention research (Philadelphia, Pa.), Vol.6(7), pp.719-730
- Academic Unit
- Pharmaceutical Sciences, Department of
- Identifiers
- 99900546824001842
- Language
- English
- Resource Type
- Journal article