Characterization of raloxifene glucuronidation: Potential role of UGT1A8 genotype on raloxifene metabolism in vivo

Dongxiao Sun, Nathan R. Jones, Andrea Manni, Philip Lazarus

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Raloxifene is a second-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 (Ptrend = 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 lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-40-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-40-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-40-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus 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.

Original languageEnglish (US)
Pages (from-to)719-730
Number of pages12
JournalCancer Prevention Research
Volume6
Issue number7
DOIs
StatePublished - Jul 2013

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Genotype
Glucuronides
UGT1A8 UDP-glucuronosyltransferase
Raloxifene Hydrochloride
Selective Estrogen Receptor Modulators
Cell Line
Liver
Liver Microsomes
Jejunum
Estrogen Receptors
Osteoporosis

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

@article{b70fa1440c924b4594267ac258a3661f,
title = "Characterization of raloxifene glucuronidation: Potential role of UGT1A8 genotype on raloxifene metabolism in vivo",
abstract = "Raloxifene is a second-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 (Ptrend = 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 lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-40-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99{\%} of the circulating raloxifene dose in raloxifene-treated subjects, with ral-40-Gluc comprising ∼70{\%} of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-40-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus 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.",
author = "Dongxiao Sun and Jones, {Nathan R.} and Andrea Manni and Philip Lazarus",
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Characterization of raloxifene glucuronidation : Potential role of UGT1A8 genotype on raloxifene metabolism in vivo. / Sun, Dongxiao; Jones, Nathan R.; Manni, Andrea; Lazarus, Philip.

In: Cancer Prevention Research, Vol. 6, No. 7, 07.2013, p. 719-730.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Characterization of raloxifene glucuronidation

T2 - Potential role of UGT1A8 genotype on raloxifene metabolism in vivo

AU - Sun, Dongxiao

AU - Jones, Nathan R.

AU - Manni, Andrea

AU - Lazarus, Philip

PY - 2013/7

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N2 - Raloxifene is a second-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 (Ptrend = 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 lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-40-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-40-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-40-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus 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.

AB - Raloxifene is a second-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 (Ptrend = 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 lines overexpressing UGT1A8 variants, the UGT1A8*2 variant was significantly (P = 0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-40-Gluc exhibited 1:100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised about 99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-40-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (Ptrend = 0.0025), ral-40-Gluc (Ptrend = 0.001), and total raloxifene glucuronides (Ptrend = 0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] versus intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] versus 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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