Bioactivation of bisphenol A and its analogs (BPF, BPAF, BPZ and DMBPA) in human liver microsomes

Schmidt, Jan; Kotnik, Petra; Trontelj, Jurij; Knez, Željko; Mašič, Lucija Peterlin

doi:10.1016/j.tiv.2013.02.016

Cited by 80 publications

(67 citation statements)

References 31 publications

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“…In addition, we observed that HLM could catalyze the formation of hydroxylated BPAF in the presence of NADPH (Figure 3A), which is consistent with Schmidt et al’s report [18]. However, the rate of hydroxylation is obviously slower than that of glucuronidation, because the response value of BPAF did not change substantially from 0 to 90 min (Figure 3B).…”

Section: Resultssupporting

confidence: 90%

“…Moreover, BPA also could be metabolized to 3-hydroxy BPA and BPA o-quinone by cytochrome P450s in vitro [16,17]. Recently, Schmidt et al reported that P450 could mediate biotransformation of BPAF to hydroxylated BPAF, followed by the central carbon bridge degradation which product 4-hexafluorohydroxyisopropylidene-phenol as the main metabolite in the presence of human liver microsomes (HLM) with NADPH and GSH in vitro [18]. However, the biotransformation of BPAF in vivo and the estrogenic effect of its metabolites remain unknown.…”

Section: Introductionmentioning

confidence: 99%

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Biotransformation of Bisphenol AF to Its Major Glucuronide Metabolite Reduces Estrogenic Activity

Yang

et al. 2013

PLoS ONE

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Bisphenol AF (BPAF), an endocrine disrupting chemical, can induce estrogenic activity through binding to estrogen receptor (ER). However, the metabolism of BPAF in vivo and the estrogenic activity of its metabolites remain unknown. In the present study, we identified four metabolites including BPAF diglucuronide, BPAF glucuronide (BPAF-G), BPAF glucuronide dehydrated and BPAF sulfate in the urine of Sprague-Dawley (SD) rats. BPAF-G was further characterized by nuclear magnetic resonance (NMR). After treatment with a single dose of BPAF, BPAF was metabolized rapidly to BPAF-G, as detected in the plasma of SD rats. Biotransformation of BPAF to BPAF-G was confirmed with human liver microsomes (HLM), and Vmax of glucuronidation for HLM was 11.6 nmol/min/mg. We also found that BPAF glucuronidation could be mediated through several human recombinant UDP-glucuronosyltransferases (UGTs) including UGT1A1, UGT1A3, UGT1A8, UGT1A9, UGT2B4, UGT2B7, UGT2B15 and UGT2B17, among which UGT2B7 showed the highest efficiency of glucuronidation. To explain the biological function of BPAF biotransformation, the estrogenic activities of BPAF and BPAF-G were evaluated in ER-positive breast cancer T47D and MCF7 cells. BPAF significantly stimulates ER-regulated gene expression and cell proliferation at the dose of 100 nM and 1 μM in breast cancer cells. However, BPAF-G did not show any induction of estrogenic activity at the same dosages, implying that formation of BPAF-G is a potential host defense mechanism against BPAF. Based on our study, biotransformation of BPAF to BPAF-G can eliminate BPAF-induced estrogenic activity, which is therefore considered as reducing the potential threat to human beings.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Biotransformation of Bisphenol AF to Its Major Glucuronide Metabolite Reduces Estrogenic Activity

Yang

et al. 2013

PLoS ONE

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“…However, the effect of BPE was less persistent than that of BPA. As different enzymes are responsible for the hydroxylation of the different bisphenols (Schmidt et al, 2013), BPE may be biotransformed more efficiently than BPA in the human testis. In our study, a lower concentration of BPF (10 -6 M) had an inhibitory dose effect on testosterone production.…”

Section: Inhibin Bmentioning

confidence: 99%

Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis

et al. 2017

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WHAT IS KNOWN ALREADY:The few epidemiologic studies performed suggest that bisphenols have potential endocrine disruptive properties, but they did not identify clear and direct patterns of endocrine disruption. STUDY DESIGN, SIZE, DURATION:Adult human testis explants in culture were exposed to BPA and the analogs bisphenol F (BPF), bisphenol S (BPS), bisphenol E (BPE), bisphenol B (BPB), and bisphenol A diglycidyl ether (BADGE) at 10 -9 to 10 -5 M for 24 h or 48h.PARTICIPANTS/MATERIALS, SETTING, METHODS: Human adult testes were obtained from prostate cancer patients who had no hormone therapy, or from multiorgan donors. After ex vivo exposure to the investigated bisphenols, the measured outcomes were related to histopathology (gross morphology and germ cell viability determined by anti-caspase 3 immunohistochemistry), and the levels of testosterone, insulin-like fator 3 and inhibin B were measured using immunoassays. The levels of mRNA encoding key enzymes of bisphenol biotransformation were investigated by quantitative PCR: UGT2B15 UDP (glucuronosyltransferase two family, polypeptide B15), GUSB (glucuronidase beta), SULT1A1 and 3 (sulfotransferase family 1 A member 1 and 3) and STS (steroid sulfatase). MAIN RESULTS AND THE ROLE OF CHANCE: A significant dose-dependent inhibition wasfound between testosterone levels measured in the culture medium and concentrations of BPA The active concentrations of BPA and BPA-A used in the study were higher than those found in human biological fluids. WIDER IMPLICATIONS OF THE FINDINGS:Under our experimental conditions, direct exposure to BPA or BPA-A can result in endocrine disturbance in the adult human testis.

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“…The metabolism of other allyl-benzene compounds, such as safrole and estragole, can also result in 1'-hydroxy derivatives [26,27]. In addition, terminal olefins are usually converted to epoxides, which are considered to be an active intermediate substructure after metabolic activation [26,28]. Therefore, the identity of metabolite M2 may be 1'-hydroxymyristicin or 2',3'-epoxy-myristicin.…”

Section: Phase I Metabolism-identification Of the Metabolitesmentioning

confidence: 99%

Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2

Yang

Chen

et al. 2015

Chemico-Biological Interactions

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Bioactivation of bisphenol A and its analogs (BPF, BPAF, BPZ and DMBPA) in human liver microsomes

Cited by 80 publications

References 31 publications

Biotransformation of Bisphenol AF to Its Major Glucuronide Metabolite Reduces Estrogenic Activity

Biotransformation of Bisphenol AF to Its Major Glucuronide Metabolite Reduces Estrogenic Activity

Parallel assessment of the effects of bisphenol A and several of its analogs on the adult human testis

Identification and characterization of reactive metabolites in myristicin-mediated mechanism-based inhibition of CYP1A2

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