Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants

Sun, Dongxiao; Chen, Gang; Dellinger, Ryan W.; Duncan, Kimberly; Fang, Jia Long; Lazarus, Philip

doi:10.1186/bcr1539

Cited by 80 publications

(101 citation statements)

References 35 publications

(49 reference statements)

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“…This polymorphism has functional effects toward the anticancer drug tamoxifen (Sun et al, 2006) and the atypical antipsychotic clozapine (Mori et al, 2005). Both of these studies reported apparently higher intrinsic clearances (V max /K m ratios) for the polymorphism due to lower K m values being reported.…”

Section: Miyagi and Colliermentioning

confidence: 89%

Pediatric Development of Glucuronidation: The Ontogeny of Hepatic UGT1A4

Miyagi¹,

Collier²

2007

Drug Metab Dispos

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ABSTRACT:This article reports on the development of UDP-glucuronosyltransferase (UGT) enzyme activity in pediatric livers. The substrates 4-methylumbelliferone (4MU) and trifluoperazine (TFP) were used as probes for general glucuronidation and specific UGT1A4 activity, respectively. The activity of hepatic ␤-glucuronidase enzymes was also determined so as to investigate the balance between glucuronide clearance and systemic recirculation. UGT activity toward 4MU reached maximum levels by 20 months of age, whereas the activity of ␤-glucuronidase was highest in the neonatal liver and decreased to steady-state adult levels by 4 months. The average V max and K m values for UGT1A4 in pediatric samples were 151.9 ؎ 63.5 pmol/min/mg protein and 14.4 ؎ 9.6 M, respectively. Average V max was understandably low because of developmental dynamics, but K m was similar to values reported elsewhere.When a constant rate of enzyme development is assumed, maximum activity of UGT1A4 occurs at 1.4 years of age. When the intrinsic hepatic clearance of TFP was scaled with an allometric model, hepatic clearance of TFP by UGT1A4 did not reach maximum levels until 18.9 years of age and scaled results underestimated reported in vivo clearances in adult males. No significant differences in UGT activities or hepatic clearance were observed with gender or ethnicity. The developmental dynamics of most drug-metabolizing enzymes are unknown, and this article contains, to our knowledge, the first description of the development of a single UGT isoform in childhood. Ultimately, work such as this is important for predicting drug responses and for developing and evaluating new medications in children.

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Section: Miyagi and Colliermentioning

confidence: 89%

Pediatric Development of Glucuronidation: The Ontogeny of Hepatic UGT1A4

Miyagi¹,

Collier²

2007

Drug Metab Dispos

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“…For therapeutic purposes, some synthetic compounds, such as tamoxifen (TAM) and its metabolite trans-hydroxytamoxifen, are used as antiestrogen drugs [20]; flutamide (FLU) is the most commonly used antiandrogen drug. Various nontarget environmental contaminants also display antagonism to estrogen or androgen receptors.…”

Section: Introductionmentioning

confidence: 99%

Screening of multiple hormonal activities in surface water and sediment from the Pearl River system, South China, using effect‐directed in vitro bioassays

Zhao

Ying

Yang

et al. 2011

Enviro Toxic and Chemistry

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Abstract-This paper reports screening of multiple hormonal activities (estrogenic and androgenic activities, antiestrogenic and antiandrogenic activities) for surface water and sediment from the Pearl River system (Liuxi, Zhujiang, and Shijing rivers) in South China, using in vitro recombinant yeast bioassays. The detection frequencies for estrogenic and antiandrogenic activities were both 100% in surface water and 81 and 93% in sediment, respectively. The levels of estrogenic activity were 0.23 to 324 ng 17b-estradiol equivalent concentration (EEQ)/L in surface water and 0 to 101 ng EEQ/g in sediment. Antiandrogenic activities were in the range of 20.4 to 935 Â 10 3 ng flutamide equivalent concentration (FEQ)/L in surface water and 0 to 154 Â 10 3 ng FEQ/g in sediment. Moreover, estrogenic activity and antiandrogenic activity in sediment showed good correlation (R 2 ¼ 0.7187), suggesting that the agonists of estrogen receptor and the antagonists of androgen receptor co-occurred in sediment. The detection frequencies for androgenic and antiestrogenic activities were 41 and 29% in surface water and 61 and 4% in sediment, respectively. The levels of androgenic activities were 0 to 45.4 ng dihydrotestosterone equivalent concentration (DEQ)/L in surface water, and the potency was very weak in the only detected sediment site. The levels of antiestrogenic activity were 0 to 1,296 Â 10 3 ng tamoxifen equivalent concentration (TEQ)/L in surface water and 0 to 89.5 Â 10 3 ng TEQ/g in sediment. The Shijing River displayed higher levels of hormonal activities than the Zhujiang and Liuxi rivers, indicating that the Shijing River had been suffering from heavy contamination with endocrine-disrupting chemicals. The equivalent concentrations of hormonal activities in some sites were greater than the lowest-observed-effect concentrations reported in the literature, suggesting potential adverse effects on aquatic organisms. Environ.

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“…The gradient elution conditions for kinetic assays with trans-or cis-4-OH-TAM was as follows: starting with 75% buffer A (100 mM ammonium acetate; pH 5.0) and 25% acetonitrile, the flow rate was maintained at 0.5 ml/min over 5 min; a subsequent linear gradient to 75% acetonitrile/25% buffer A over 25 min was performed and then maintained at 75% acetonitrile for 10 min. trans-4-OH-TAM-N ϩ -glucuronide, trans-4-OH-TAM-O-glucuronide, cis-4-OH-TAM-N ϩ -glucuronide, and cis-4-OH-TAM-O-glucuronide were confirmed by 1 M NaOH hydrolysis, and sensitivity to ␤-glucuronidase as described previously (Sun et al, 2006). For characterization of endoxifen glucuronides, the gradient elution conditions were the same as the gradient programs described above except that the pH of buffer A was For kinetic assays of trans-or cis-endoxifen-Oglucuronide formation, the pH of buffer A was kept at 5.0 for better resolution, and all of the analytical conditions were the same as those for 4-OH-TAM as described above.…”

Section: Synthesis Of Cis/trans-4-oh-n-desmethyltam (Cis/trans-endoximentioning

confidence: 99%

“…Microsomes from human liver specimens exhibit high glucuronidating activities toward TAM to form TAM-N ϩ -glucuronide and both the trans-and cis-isomers of 4-OH-TAM to form 4-OH-TAM-N ϩ -and 4-OH-TAM-O-glucuronides (Sun et al, 2006). One of the UGTs involved in the glucuronidation of TAM and its metabolites is the hepatic enzyme UGT1A4 (Nishiyama et al, 2002;Kaku et al, 2004), which catalyzes the formation of a quaternary ammoniumlinked glucuronide with the N,N-dimethylamino alkyl side chain of TAM or 4-OH-TAM (Kaku et al, 2004).…”

Section: -[4-(2-dimethylaminoethoxy)-phenyl]-12-diphenylbut-1(z)-enmentioning

confidence: 99%

Glucuronidation of Active Tamoxifen Metabolites by the Human UDP Glucuronosyltransferases

Sun¹,

Sharma²,

Dellinger³

et al. 2007

Drug Metab Dispos

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116

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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 ϳ 1A8 > UGT1A10 exhibited the highest overall O-glucuronidating activity against trans-4-OH-TAM as determined by V max /K M , with the hepatic enzyme UGT2B7 exhibiting the highest binding affinity and lowest K M (3.7 M). As determined by V max /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 ϳ 1A8 > UGT2B7 exhibited the highest overall glucuronidating activities as determined by V max /K M for trans-endoxifen, with the extrahepatic enzyme UGT1A10 exhibiting the highest binding affinity and lowest K M (39.9 M). 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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Characterization of tamoxifen and 4-hydroxytamoxifen glucuronidation by human UGT1A4 variants

Cited by 80 publications

References 35 publications

Pediatric Development of Glucuronidation: The Ontogeny of Hepatic UGT1A4

Pediatric Development of Glucuronidation: The Ontogeny of Hepatic UGT1A4

Screening of multiple hormonal activities in surface water and sediment from the Pearl River system, South China, using effect‐directed in vitro bioassays

Glucuronidation of Active Tamoxifen Metabolites by the Human UDP Glucuronosyltransferases

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