Regioselective glucuronidation of gingerols by human liver microsomes and expressed UDP-glucuronosyltransferase enzymes: reaction kinetics and activity correlation analyses for UGT1A9 and UGT2B7

Wu, Zhufeng; Li, Hongming; Wu, Baojian

doi:10.1111/jphp.12351

Cited by 13 publications

(18 citation statements)

References 42 publications

(92 reference statements)

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“…Our finding that UGT1A9 and UGT2B7 made significant contributions to metabolism of alcoholic curcumin analogs (RAO-3 and RAO-18) were consistent with previous studies in which the two enzymes show marked activities toward hexahydro-curcuminoids and alcoholic gingerols (a class of curcumin structurally related compounds) Wu et al, 2015). In fact, UGT1A9 and UGT2B7 showed glucuronidation activities toward a broad range of compounds containing an alcoholic hydroxyl group.…”

Section: Glucuronidation Kinetics By Recombinant Ugt Enzymessupporting

confidence: 91%

Structure- and isoform-specific glucuronidation of six curcumin analogs

Hui

et al. 2016

Xenobiotica

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1. In the present study, we aimed to characterize the glucuronidation of six curcumin analogs (i.e. RAO-3, RAO-8, RAO-9, RAO-18, RAO-19, and RAO-23) derived from galangal using human liver microsomes (HLM) and twelve expressed UGT enzymes. 2. Formation of glucuronide was confirmed using high-resolution mass spectrometry. Single glucuronide metabolite was generated from each of six curcumin analogs. The fragmentation patterns were analyzed and were found to differ significantly between alcoholic and phenolic glucuronides. 3. All six curcumin analogs except one (RAO-23) underwent significant glucuronidation in HLM and expressed UGT enzymes. In general, the methoxy group (close to the phenolic hydroxyl group) enhanced the glucuronidation liability of the curcumin analogs. 4. UGT1A9 and UGT2B7 were primarily responsible for the glucuronidation of two alcoholic analogs (RAO-3 and RAO-18). By contrast, UGT1A9 and four UGT2Bs (UGT2B4, 2B7, 2B15 and 2B17) played important roles in conjugating three phenolic analogs (RAO-8, RAO-9, and RAO-19). Interestingly, the conjugated double bonds system (in the aliphatic chain) was crucial to the substrate selectivity of gastrointestinal UGTs (i.e. UGT1A7, 1A8 and 1A10). 5. In conclusion, glucuronidation of six curcumin analogs from galangal were structure- and isoform-specific. The knowledge should be useful in identifying a curcumin analog with improved metabolic property.

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Section: Glucuronidation Kinetics By Recombinant Ugt Enzymessupporting

confidence: 91%

Structure- and isoform-specific glucuronidation of six curcumin analogs

Hui

et al. 2016

Xenobiotica

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“…UGT1A9, together with UGT1A1, were also reported to play an important role in the liver glucuronidation of the soybean isoflavones genistein and daidzein, molecules with protective effects against certain types of cancer and possibly roles in tumour prevention . Recent data have also expanded the repertoire of UGT1A9 substrates that exhibit antioxidant, anti‐inflammatory, hepatoprotective and antitumour activities …”

Section: Discussionmentioning

confidence: 99%

“…35 Recent data have also expanded the repertoire of UGT1A9 substrates that exhibit antioxidant, anti-inflammatory, hepatoprotective and antitumour activities. 36,37 UGT1A7*3 allele, which results in the production of an enzyme with a 50% reduction in catalytic activity, 13 emerged as a further marker of HCC susceptibility, displaying a protective role against liver cancer development. In this study, for the first time, UGT1A7*3 allele was found to be significantly associated with the likelihood to develop HCC also in HBV-and HCV-positive subgroups.…”

Section: Discussionmentioning

confidence: 99%

UGT1A polymorphisms as genetic biomarkers for hepatocellular carcinoma risk in Caucasian population

Mattia

Cecchin

Polesel

et al. 2017

Liver International

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“…The elucidation of regioselectivity by kinetic determination was superior to that by rate determination at high substrate concentrations [31]. In addition, the use of CL int as indicator of UGT activity was more advantageous than the use of reaction rates because CL int is more relevant in predicting hepatic clearance in vivo compared with other kinetic parameters [32,33]. In HLMs, the CL int value of diosmetin through 3′-OH was much higher than that of the 7-OH, and the CL int value of chrysoeriol through 4′-OH was about 32 times than that of the 7-OH pathway.…”

Section: Discussionmentioning

confidence: 99%

Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

et al. 2016

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This study aimed to determine the reaction kinetics of the regioselective glucuronidation of diosmetin and chrysoeriol, two important methylated metabolites of luteolin, by human liver microsomes (HLMs) and uridine-5′-diphosphate glucuronosyltransferase (UGTs) enzymes. This study also investigated the effects of breast cancer resistance protein (BCRP) on the efflux of diosmetin and chrysoeriol glucuronides in HeLa cells overexpressing UGT1A9 (HeLa—UGT1A9). After incubation with HLMs in the presence of UDP-glucuronic acid, diosmetin and chrysoeriol gained two glucuronides each, and the OH—in each B ring of diosmetin and chrysoeriol was the preferable site for glucuronidation. Screening assays with 12 human expressed UGT enzymes and chemical-inhibition assays demonstrated that glucuronide formation was almost exclusively catalyzed by UGT1A1, UGT1A6, and UGT1A9. Importantly, in HeLa—UGT1A9, Ko143 significantly inhibited the efflux of diosmetin and chrysoeriol glucuronides and increased their intracellular levels in a dose-dependent manner. This observation suggested that BCRP-mediated excretion was the predominant pathway for diosmetin and chrysoeriol disposition. In conclusion, UGT1A1, UGT1A6, and UGT1A9 were the chief contributors to the regioselective glucuronidation of diosmetin and chrysoeriol in the liver. Moreover, cellular glucuronidation was significantly altered by inhibiting BCRP, revealing a notable interplay between glucuronidation and efflux transport. Diosmetin and chrysoeriol possibly have different effects on anti-cancer due to the difference of UGT isoforms in different cancer cells.

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Regioselective glucuronidation of gingerols by human liver microsomes and expressed UDP-glucuronosyltransferase enzymes: reaction kinetics and activity correlation analyses for UGT1A9 and UGT2B7

Abstract: Gingerols were metabolized by multiple hepatic and gastrointestinal UGT enzymes. Also, UGT1A9 and 2B7 were the main contributors to regioselective glucuronidation of gingerols in the liver.

Cited by 13 publications

References 42 publications

Structure- and isoform-specific glucuronidation of six curcumin analogs

Structure- and isoform-specific glucuronidation of six curcumin analogs

UGT1A polymorphisms as genetic biomarkers for hepatocellular carcinoma risk in Caucasian population

Regioselective Glucuronidation of Diosmetin and Chrysoeriol by the Interplay of Glucuronidation and Transport in UGT1A9-Overexpressing HeLa Cells

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