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 17-dihydroexemestane glucuronidation. METHODS:Homogenates from a HEK293 aromatase-overexpressing cell line (HEK293-aro) were used to examine exemestane versus 17-dihydroexemestane anti-aromatase activities. UGT-overexpressing cell lines and a panel (n=110) of human liver microsome (HLM) were screened for glucuronidation activity against 17-dihydroexemestane. UGT2B17 genotyping and liver mRNA expression were performed by real-time PCR. RESULTS:The inhibition of estrone formation from androst-4-ene-3,17-dione in HEK293-aro cell homogenates was similar for 17-dihydroexemestane (IC(50)=2.3±0.83 μmol/l) and exemestane (IC(50)=1.4±0.42 μmol/l). UGTs 2B17 and 1A4 were high-expression hepatic UGTs that exhibited activity against 17-dihydroexemestane, with UGT2B17 exhibiting a 17-fold higher V(max)/K(M) than UGT1A4. The rate of exemestane-17-O-glucuronide formation was shown to be significantly (P<0.001) decreased (14-fold) in HLMs exhibiting the UGT2B17(*2/*2) deletion genotype versus wild-type UGT2B17(*1/*1) HLMs; a 36-fold lower V(max)/K(M) (P=0.023) was observed in UGT2B17(*2/*2) versus UGT2B17(*1/*1) HLMs. A significant (P<0.0001, R(2)=0.72) correlation was observed between HLM exemestane-17-O-glucuronide formation and liver UGT2B17 expression. CONCLUSION:These data suggest that 17-dihydroexemestane is an active metabolite of exemestane and that the UGT2B17 deletion polymorphism could play an important role in determining levels of excretion of 17-dihydroexemestane and overall exemestane metabolism.
journal_name
Pharmacogenet Genomicsjournal_title
Pharmacogenetics and genomicsauthors
Sun D,Chen G,Dellinger RW,Sharma AK,Lazarus Pdoi
10.1097/FPC.0b013e32833b04afsubject
Has Abstractpub_date
2010-10-01 00:00:00pages
575-85issue
10eissn
1744-6872issn
1744-6880journal_volume
20pub_type
杂志文章abstract:OBJECTIVES:Multiple sclerosis (MS) is a neurodegenerative chronic inflammatory. Mutations in the vitamin D receptor (VDR) gene can substantially affect serum vitamin D levels or alter its functionality, and can consequently increase susceptibility to developing MS. The objective of this study was to evaluate the associ...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000420
更新日期:2021-02-01 00:00:00
abstract:BACKGROUND:For prevention of joint destruction in rheumatoid arthritis, optimal management of therapy with disease-modifying antirheumatic drugs is essential. Pharmacogenomic evidence, if reliable, may be incorporated in the treatment of rheumatoid arthritis to achieve a more efficient activity control with minimized a...
journal_title:Pharmacogenetics and genomics
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doi:10.1097/01.fpc.0000236326.80809.b1
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abstract::A possible association between the combination of genetic variations in hepatocyte nuclear factor 4α (HNF4α) and constitutive androstane receptor (CAR) and the stable doses of warfarin was examined in patients from the Ewha-Severance Treatment (EAST) Group of Warfarin. Around 42.5% of the overall interindividual varia...
journal_title:Pharmacogenetics and genomics
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e328335731c
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abstract:PURPOSE:Polymorphisms in genes encoding subunits of heterotrimeric G proteins have been repeatedly associated with various cancers. As G beta gamma signaling is presumed to be involved in proliferation and invasion processes, we analyzed genetic variations in regulatory regions of GNB4, which encodes the G beta 4 subun...
journal_title:Pharmacogenetics and genomics
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abstract:OBJECTIVE:A meta-analysis was carried out of published studies on the effect of the CYP3A5 6986A>G polymorphism in liver donors and transplant recipients on tacrolimus pharmacokinetics. METHODS:Cohort studies that evaluated the relationship between the CYP3A5 polymorphism in liver donors and transplant recipients and ...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,meta分析,评审
doi:10.1097/FPC.0b013e3283642fb3
更新日期:2013-10-01 00:00:00
abstract:OBJECTIVES:A total of 2402 patients with arsenic-related skin lesions, such as hyperkeratosis, hyperpigmentation or hypopigmentation, or even skin cancer in a few villages in Southwest Guizhou Autonomous Prefecture, China represent a unique case of endemic arsenism related with indoor combustion of high arsenic coal. T...
journal_title:Pharmacogenetics and genomics
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更新日期:2006-12-01 00:00:00
abstract:OBJECTIVES:Epidemiological studies documented associations between single nucleotide polymorphisms (SNPs) in the nucleotide excision repair gene XPD/ERCC2 and cancer risk. Little is known, however, about the underlying mechanisms for these associations. We explored a novel mechanism that could further explain the repor...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e3280115e63
更新日期:2007-11-01 00:00:00
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journal_title:Pharmacogenetics and genomics
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doi:10.1097/FPC.0b013e3283544085
更新日期:2012-08-01 00:00:00
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更新日期:2008-06-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,随机对照试验
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更新日期:2015-12-01 00:00:00
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journal_title:Pharmacogenetics and genomics
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doi:10.1097/FPC.0b013e32832cbe61
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doi:10.1097/FPC.0b013e3282f4e98c
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journal_title:Pharmacogenetics and genomics
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doi:10.1097/FPC.0b013e328363176f
更新日期:2013-08-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,meta分析,评审
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更新日期:2014-07-01 00:00:00
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journal_title:Pharmacogenetics and genomics
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doi:10.1097/FPC.0b013e3283367c6b
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pub_type: 临床试验,杂志文章,多中心研究
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章,评审
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更新日期:2011-07-01 00:00:00
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journal_title:Pharmacogenetics and genomics
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更新日期:2012-04-01 00:00:00
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doi:10.1097/FPC.0b013e328301a763
更新日期:2008-07-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e32835a0ffa
更新日期:2013-04-01 00:00:00
abstract:BACKGROUND:Genetic variants appear to influence, at least to some degree, the extent of brain injury and the clinical outcome of patients who have sustained a traumatic brain injury (TBI). Angiotensin-converting enzyme (ACE) is a zinc metallopeptidase that is implicated in the regulation of blood pressure and cerebral ...
journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0000000000000161
更新日期:2015-10-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
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更新日期:2014-02-01 00:00:00
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journal_title:Pharmacogenetics and genomics
pub_type: 杂志文章
doi:10.1097/FPC.0b013e3282f974b7
更新日期:2008-04-01 00:00:00
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更新日期:2017-07-01 00:00:00
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更新日期:2011-06-01 00:00:00
abstract::Two recent screens for copy-number variations in the entire human genome found 12.4 gene copy number variations per person, including 2.5% of individuals with gains between 7q21.1 and 7q22.1, the chromosomal location of CYP3A4. CYP3A4 is involved in the metabolism of approximately 50% of all drugs, including many canc...
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更新日期:2006-06-01 00:00:00