2010
DOI: 10.1097/fpc.0b013e32833b04af
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Characterization of 17-dihydroexemestane glucuronidation: potential role of the UGT2B17 deletion in exemestane pharmacogenetics

Abstract: Objective Exemestane is a third-generation aromatase inhibitor used in the treatment of breast cancer in postmenopausal women. Reduction to form 17-dihydroexemestane and subsequent glucuronidation to exemestane-17-O-glucuronide is a major pathway for exemestane metabolism. The goal of this study was to analyze 17-dihydroexemestane anti-aromatase activity, characterize the 17-dihydroexemestane glucuronidation pathway, and determine whether the functional polymorphisms in active UGTs could play a role in altered… Show more

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Cited by 53 publications
(79 citation statements)
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“…UGT2B17 was shown previously to exhibit the highest glucuronidation activity of any hepatic UGT tested against 17-DHE, 3-HC, and SAHA (Balliet et al, 2009;Sun et al, 2010; G. Chen, N. Giambrone, R. M. Balliet, and P. Lazarus, submitted for publication), so those substrates were the focus of the glucuronidation studies by sex in this study. When we stratified by sex, significantly higher amounts of exemestane-17-O-glucuronide formation were observed in individuals with either one or two copies of UGT2B17 than in individuals with 0 copies of UGT2B17 for both women ( p ϭ 0.045 and 0.001, respectively) and men ( p Ͻ 0.001 for both) (Fig.…”
Section: Resultsmentioning
confidence: 89%
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“…UGT2B17 was shown previously to exhibit the highest glucuronidation activity of any hepatic UGT tested against 17-DHE, 3-HC, and SAHA (Balliet et al, 2009;Sun et al, 2010; G. Chen, N. Giambrone, R. M. Balliet, and P. Lazarus, submitted for publication), so those substrates were the focus of the glucuronidation studies by sex in this study. When we stratified by sex, significantly higher amounts of exemestane-17-O-glucuronide formation were observed in individuals with either one or two copies of UGT2B17 than in individuals with 0 copies of UGT2B17 for both women ( p ϭ 0.045 and 0.001, respectively) and men ( p Ͻ 0.001 for both) (Fig.…”
Section: Resultsmentioning
confidence: 89%
“…3-Hydroxycotinine (3-HC), 3-HC glucuronide, and deuterium-labeled internal standards cotinine-(methyl-D 3 )-3Ј-O-glucuronide were purchased from Toronto Research Chemicals Inc. (North York, ON, Canada). Structures of all compounds were provided in previous publications (Balliet et al, 2009;Sun et al, 2010; Chen, N. Giambrone, R. M. Balliet, and P. Lazarus, submitted for publication). UDP-glucuronic acid, alamethicin, and ␤-glucuronidase were purchased from Sigma-Aldrich (St. Louis, MO).…”
Section: Methodsmentioning
confidence: 99%
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“…The UDP-glucuronosyltransferase (UGT) family of phase II metabolic enzymes play a central role in the excretion of numerous endogenous compounds, including bilirubin (Bosma et al, 1994) and steroid hormones (Belanger et al, 1998(Belanger et al, , 2003, as well as exogenous compounds, including various drugs (Nagar and Remmel, 2006) and chemotherapeutic agents (Kemp et al, 2002;Sun et al, 2006Sun et al, , 2007Sun et al, , 2010Balliet et al, 2009). The UGTs also play an important role in the metabolism and detoxification of multiple tobacco carcinogens, including tobacco-specific nitrosamines like 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) (Ren et al, 2000;Wiener et al, 2004a;Chen et al, 2008b), and polycyclic aromatic hydrocarbons like benzo(a)pyrene [B(a)P]-7,8-diol and dibenzo(a,l)pyrene-11,12-diol [DB(a,l)P] (Fang et al, 2002;Olson et al, 2011).…”
Section: Introductionmentioning
confidence: 99%