Inhibition of Genistein Glucuronidation by Bisphenol A in Human and Rat Liver Microsomes

Coughlin, Janis L.; Thomas, Paul E.; Buckley, Brian

doi:10.1124/dmd.111.042366

Cited by 19 publications

(20 citation statements)

References 27 publications

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“…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. For another, the K m values of diosmetin and chrysoeriol glucuronides were lower than a series of 7-OH, 3’-OH or 4’-OH flavonoids, such as acacetin glucuronide (K m was 14.465 μM)[34] and genistein glucuronides (K m was 15.1 μM)[35] (Table 1). …”

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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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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“…In the present study, the rate of reaction for both glucuronidation and sulfation for the PBPK model was derived by IVIVE scaling approach. The current hepatic in-vitro cell line data were used for deriving maximum reaction velocity (Coughlin et al, 2012) using equation 9that accounts microsomal protein value (32mg/g of liver) and liver weight (2.6 percentage of BW). The metabolism was described based on Michaelis-Menten equations using equation 6 119 (adult liver), 17.8 ± 1.8 (mid-term placenta) and 17.0 ± 1.7 (near term placenta) (Beach et al, 1978;Cappiello et al, 2000;Coughtrie et al, 1988;Kawade and Onishi, 1981).…”

Section: Metabolism In the Adult Livermentioning

confidence: 99%

“…considering Vmax and Km value from an in-vitro hepatic cell line (Coughlin et al, 2012). The in-vivo Vmax for the placenta was calculated using placenta microsomal content i.e., 11.3 mg/g (McLaughlin et al, 2000), placenta volume and the body weight.…”

Section: Bpagmentioning

confidence: 99%

The development of a pregnancy PBPK Model for Bisphenol A and its evaluation with the available biomonitoring data

Sharma

Schuhmacher

Kumar

2018

Science of The Total Environment

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Recent studies suggest universal fetal exposure to Bisphenol A (BPA) and its association with the adverse birth outcomes. Estimation of the fetal plasma BPA concentration from the maternal plasma BPA would be highly useful to predict its associated risk to this specific population. The objective of current work is to develop a pregnancy-physiologically based pharmacokinetic (P-PBPK) model to predict the toxicokinetic profile of BPA in the fetus during gestational growth, and to evaluate the developed model using biomonitoring data obtained from different pregnancy cohort studies. To achieve this objective, first, the adult PBPK model was developed and validated with the human BPA toxicokinetic data. This validated human PBPK model was extended to develop a P-PBPK model, which included the physiological changes during pregnancy and the fetus sub-model. The developed model would be able to predict the BPA pharmacokinetics (PKs) in both mother and fetus. Transplacental BPA kinetics parameters for this study were taken from the previous pregnant mice study. Both oral and dermal exposure routes were included into the model to simulate total BPA internal exposure. The impact of conjugation and deconjugation of the BPA and its metabolites on fetal PKs was investigated. The developed P-PBPK model was evaluated against the observed BPA concentrations in cord blood, fetus liver and amniotic fluid considering maternal blood concentration as an exposure source. A range of maternal exposure dose for the oral and dermal routes was estimated, so that simulation concentration matched the observed highest and lowest mother plasma concentration in different cohorts' studies. The developed model could be used to address the concerns regarding possible adverse health effects in the fetus being exposed to BPA and might be useful in identifying critical windows of exposure during pregnancy.

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“…The decline in the expression of transporters with gestational age is further corroborated by the increased rate of placental transfer and amount of P-gp substrates during late pregnancy compared to early pregnancy [ 96 ]. Some TH-EDC chemicals may alter other metabolic pathways thereby modulating the effect of metabolizing enzymes on endogenous substrates like steroid hormones [ 92 ] or other xenobiotics [ 97 ].…”

Section: Resultsmentioning

confidence: 99%

“…A similar study on term human placentas revealed that genistein, a naturally occurring phytoestrogen was able to traverse the placental barrier although only a small proportion was biotransformed by metabolizing enzymes in the placenta [ 99 ]. BPA and genistein both share similar metabolic pathways as well as estrogen disrupting effects [ 97 ]. UGT activity has been shown to be higher in human first trimester placenta compared to term placentas [ 94 ] and to decrease as pregnancy advances in humans [ 93 ].…”

Section: Resultsmentioning

confidence: 99%

Prenatal Exposures to Multiple Thyroid Hormone Disruptors: Effects on Glucose and Lipid Metabolism

Molehin

Nitert

Richard

2016

Journal of Thyroid Research

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Background. Thyroid hormones (THs) are essential for normal human fetal development and play a major role in the regulation of glucose and lipid metabolism. Delivery of TH to target tissues is dependent on processes including TH synthesis, transport, and metabolism. Thyroid hormone endocrine disruptors (TH-EDCs) are chemical substances that interfere with these processes, potentially leading to adverse pregnancy outcomes. Objectives. This review focuses on the effects of prenatal exposures to combinations of TH-EDCs on fetal and neonatal glucose and lipid metabolism and also discusses the various mechanisms by which TH-EDCs interfere with other hormonal pathways. Methods. We conducted a comprehensive narrative review on the effects of TH-EDCs with particular emphasis on exposure during pregnancy. Discussion. TH imbalance has been linked to many metabolic processes and the effects of TH imbalance are particularly pronounced in early fetal development due to fetal dependence on maternal TH for proper growth and development. The pervasive presence of EDCs in the environment results in ubiquitous exposure to either single or mixtures of EDCs with deleterious effects on metabolism. Conclusions. Further evaluation of combined effects of TH-EDCs on fetal metabolic endpoints could improve advice provided to expectant mothers.

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Inhibition of Genistein Glucuronidation by Bisphenol A in Human and Rat Liver Microsomes

Cited by 19 publications

References 27 publications

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

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

The development of a pregnancy PBPK Model for Bisphenol A and its evaluation with the available biomonitoring data

Prenatal Exposures to Multiple Thyroid Hormone Disruptors: Effects on Glucose and Lipid Metabolism

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