Abstract
Tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA), bisphenol A (BPA) analogs, are endocrine-disrupting chemicals predominantly metabolized into glucuronides by UDP-glucuronosyltransferase (UGT) enzymes in humans and rats. In the present study, TBBPA and TCBPA glucuronidation by the liver microsomes of humans and laboratory animals (monkeys, dogs, minipigs, rats, mice, and hamsters) and recombinant human hepatic UGTs (10 isoforms) were examined. TBBPA glucuronidation by the liver microsomes followed the Michaelis–Menten model kinetics in humans, rats, and hamsters and the biphasic model in monkeys, dogs, minipigs, and mice. The CLint values based on the Eadie–Hofstee plots were mice (147) > monkeys (122) > minipigs (108) > humans (100) and rats (98) > dogs (81) > hamsters (47). TCBPA glucuronidation kinetics by the liver microsomes followed the biphasic model in all species except for minipigs, which followed the Michaelis–Menten model. The CLint values were monkeys (172) > rats (151) > mice (134) > minipigs (104), dogs (102), and humans (100) > hamsters (88). Among recombinant human UGTs examined, UGT1A1 and UGT1A9 showed higher TBBPA and TCBPA glucuronidation abilities. The kinetics of TBBPA and TCBPA glucuronidation followed the substrate inhibition model in UGT1A1 and the Michaelis–Menten model in UGT1A9. The CLint values were UGT1A1 (100) > UGT1A9 (42) for TBBPA glucuronidation and UGT1A1 (100) > UGT1A9 (53) for TCBPA glucuronidation, and the activities at high substrate concentration ranges were higher in UGT1A9 than in UGT1A1 for both TBBPA and TCBPA. These results suggest that the glucuronidation abilities toward TBBPA and TCBPA in the liver differ extensively across species, and that UGT1A1 and UGT1A9 expressed in the liver mainly contribute to the metabolism and detoxification of TBBPA and TCBPA in humans.
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References
Abou-Elwafa Abdallah M (2016) Environmental occurrence, analysis and human exposure to the flame retardant tetrabromobisphenol-A (TBBP-A)—a review. Environ Int 94:235–250. https://doi.org/10.1016/j.envint.2016.05.026
Barghi M, Shin ES, Kim JC, Choi SD, Chang YS (2017) Human exposure to HBCD and TBBPA via indoor dust in Korea: estimation of external exposure and body burden. Sci Total Environ 593–594:779–786. https://doi.org/10.1016/j.scitotenv.2017.03.200
Burchell B, Brierley CH, Rance D (1995) Specificity of human UDP-glucuronosyltransferases and xenobiotic glucuronidation. Life Sci 57:1819–1831. https://doi.org/10.1016/0024-3205(95)02073-R
Cao H, Wang F, Liang Y, Wang H, Zhang A, Song M (2017) Experimental and computational insights on the recognition mechanism between the estrogen receptor α with bisphenol compounds. Arch Toxicol 91:3897–3912. https://doi.org/10.1007/s00204-017-2011-0
Chang BV, Liu JH, Liao CS (2014) Aerobic degradation of bisphenol-A and its derivatives in river sediment. Environ Technol 35:416–424. https://doi.org/10.1080/09593330.2013.831111
Chu S, Haffner GD, Letcher RJ (2005) Simultaneous determination of tetrabromobisphenol A, tetrachlorobisphenol A, bisphenol A and other halogenated analogues in sediment and sludge by high performance liquid chromatography–electrospray tandem mass spectrometry. J Chromatogr A 1097:25–32. https://doi.org/10.1016/j.chroma.2005.08.007
Fan Z, Hu J, An W, Yang M (2013) Detection and occurrence of chlorinated byproducts of bisphenol a, nonylphenol, and estrogens in drinking water of China: comparison to the parent compounds. Environ Sci Technol 47:10841–10850. https://doi.org/10.1021/es401504a
Garoche C, Boulahtouf A, Grimaldi M, Chiavarina B, Toporova L, den Broeder MJ, Legler J, Bourguet W, Balaguer P (2021) Interspecies differences in activation of peroxisome proliferator-activated receptor γ by pharmaceutical and environmental chemicals. Environ Sci Technol 55:16489–16501. https://doi.org/10.1021/acs.est.1c04318
Hakk H, Larsen G, Bergman A, Orn U (2000) Metabolism, excretion and distribution of the flame retardant tetrabromobisphenol-A in conventional and bile-duct cannulated rats. Xenobiotica 30:881–890. https://doi.org/10.1080/004982500433309
Hanioka N, Naito T, Narimatsu S (2008) Human UDP-glucuronosyltransferase isoforms involved in bisphenol A glucuronidation. Chemosphere 74:33–36. https://doi.org/10.1016/j.chemosphere.2008.09.053
Hanioka N, Isobe T, Tanaka-Kagawa T, Jinno H, Ohkawara S (2022) In vitro glucuronidation of bisphenol A in liver and intestinal microsomes: interspecies differences in humans and laboratory animals. Drug Chem Toxicol 45:1565–1569. https://doi.org/10.1080/01480545.2020.1847133
Harbourt DE, Fallon JK, Ito S, Baba T, Ritter JK, Glish GL, Smith PC (2012) Quantification of human uridine-diphosphate glucuronosyl transferase 1A isoforms in liver, intestine, and kidney using nanobore liquid chromatography–tandem mass spectrometry. Anal Chem 84:98–105. https://doi.org/10.1021/ac201704a
Hoffmann M, Fiedor E, Ptak A (2017) Bisphenol A and its derivatives tetrabromobisphenol A and tetrachlorobisphenol A induce apelin expression and secretion in ovarian cancer cells through a peroxisome proliferator-activated receptor gamma-dependent mechanism. Toxicol Lett 269:15–22. https://doi.org/10.1016/j.toxlet.2017.01.006
Jarosiewicz M, Bukowska B (2017) Tetrabromobisphenol A: toxicity, environmental and occupational exposures. Med Pr 68:121–134. https://doi.org/10.13075/mp.5893.00491
Kitamura S, Suzuki T, Sanoh S, Kohta R, Jinno N, Sugihara K, Yoshihara S, Fujimoto N, Watanabe H, Ohta S (2005) Comparative study of the endocrine-disrupting activity of bisphenol A and 19 related compounds. Toxicol Sci 84:249–259. https://doi.org/10.1093/toxsci/kfi074
Knudsen GA, Jacobs LM, Kuester RK, Sipes IG (2007) Absorption, distribution, metabolism and excretion of intravenously and orally administered tetrabromobisphenol A [2,3-dibromopropyl ether] in male Fischer-344 rats. Toxicology 237:158–167. https://doi.org/10.1016/j.tox.2007.05.006
Knudsen GA, Sanders JM, Sadik AM, Birnbaum LS (2014) Disposition and kinetics of Tetrabromobisphenol A in female Wistar Han rats. Toxicol Rep 1:214–223. https://doi.org/10.1016/j.toxrep.2014.03.005
Kuester RK, Sólyom AM, Rodriguez VP, Sipes IG (2007) The effects of dose, route, and repeated dosing on the disposition and kinetics of tetrabromobisphenol A in male F-344 rats. Toxicol Sci 96:237–245. https://doi.org/10.1093/toxsci/kfm006
Li A, Zhuang T, Shi W, Liang Y, Liao C, Song M, Jiang G (2020) Serum concentration of bisphenol analogues in pregnant women in China. Sci Total Environ 707:136100. https://doi.org/10.1016/j.scitotenv.2019.136100
Liu K, Li J, Yan S, Zhang W, Li Y, Han D (2016) A review of status of tetrabromobisphenol A (TBBPA) in China. Chemosphere 148:8–20. https://doi.org/10.1016/j.chemosphere.2016.01.023
Lyche JL, Rosseland C, Berge G, Polder A (2015) Human health risk associated with brominated flame-retardants (BFRs). Environ Int 74:170–180. https://doi.org/10.1016/j.envint.2014.09.006
Miners JO, Mackenzie PI (1991) Drug glucuronidation in humans. Pharmacol Ther 51:347–369. https://doi.org/10.1016/0163-7258(91)90065-T
Molina-Molina JM, Amaya E, Grimaldi M, Sáenz JM, Real M, Fernández MF, Balaguer P, Olea N (2013) In vitro study on the agonistic and antagonistic activities of bisphenol-S and other bisphenol-A congeners and derivatives via nuclear receptors. Toxicol Appl Pharmacol 272:127–136. https://doi.org/10.1016/j.taap.2013.05.015
Mulder GJ, Coughtrie MWH, Burchell B (1990) Glucuronidation. In: Mulder GJ (ed) Conjugation reactions in drug metabolism. Taylor and Francis, London, pp 51–105
Nakagawa Y, Suzuki T, Ishii H, Ogata A (2007) Biotransformation and cytotoxicity of a brominated flame retardant, tetrabromobisphenol A, and its analogues in rat hepatocytes. Xenobiotica 37:693–708. https://doi.org/10.1080/00498250701397697
Nakao T, Akiyama E, Kakutani H, Mizuno A, Aozasa O, Akai Y, Ohta S (2015) Levels of tetrabromobisphenol A, tribromobisphenol A, dibromobisphenol A, monobromobisphenol A, and bisphenol a in Japanese breast milk. Chem Res Toxicol 28:722–728. https://doi.org/10.1021/tx500495j
Nakao T, Kakutani H, Yuzuriha T, Ohta S (2022) Distribution, metabolism, excretion, and lactational transfer to pups of tetrabromobisphenol A and its metabolites in C57BL/6 mice. BPB Rep 5:50–58. https://doi.org/10.1248/bpbreports.5.3_50
Ni HG, Zeng H (2013) HBCD and TBBPA in particulate phase of indoor air in Shenzhen, China. Sci Total Environ 458–460:15–19. https://doi.org/10.1016/j.scitotenv.2013.04.003
Oda S, Fukami T, Yokoi T, Nakajima M (2015) A comprehensive review of UDP-glucuronosyltransferase and esterases for drug development. Drug Metab Pharmacokinet 30:30–51. https://doi.org/10.1016/j.dmpk.2014.12.001
Ohno S, Nakajin S (2009) Determination of mRNA expression of human UDP-glucuronosyltransferases and application for localization in various human tissues by real-time reverse transcriptase-polymerase chain reaction. Drug Metab Dispos 37:32–40. https://doi.org/10.1124/dmd.108.023598
Plattard N, Venisse N, Carato P, Dupuis A, Haddad S (2022) Hepatic metabolism of chlorinated derivatives of bisphenol A (ClxBPA) and interspecies differences between rats and humans. Arch Toxicol 96:783–792. https://doi.org/10.1007/s00204-021-03217-7
Ritter JK (2000) Roles of glucuronidation and UDP-glucuronosyltransferases in xenobiotic bioactivation reactions. Chem Biol Interact 129:171–193. https://doi.org/10.1016/S0009-2797(00)00198-8
Rowland A, Miners JO, Mackenzie PI (2013) The UDP-glucuronosyltransferases: their role in drug metabolism and detoxification. Int J Biochem Cell Biol 45:1121–1132. https://doi.org/10.1016/j.biocel.2013.02.019
Sato Y, Nagata M, Tetsuka K, Tamura K, Miyashita A, Kawamura A, Usui T (2014) Optimized methods for targeted peptide-based quantification of human uridine 5′-diphosphate-glucuronosyltransferases in biological specimens using liquid chromatography–tandem mass spectrometry. Drug Metab Dispos 42:885–889. https://doi.org/10.1124/dmd.113.056291
Schauer UM, Völkel W, Dekant W (2006) Toxicokinetics of tetrabromobisphenol a in humans and rats after oral administration. Toxicol Sci 91:49–58. https://doi.org/10.1093/toxsci/kfj132
Song M, Liang D, Liang Y, Chen M, Wang F, Wang H, Jiang G (2014) Assessing developmental toxicity and estrogenic activity of halogenated bisphenol A on zebrafish (Danio rerio). Chemosphere 112:275–281. https://doi.org/10.1016/j.chemosphere.2014.04.084
Szymańska JA, Sapota A, Frydrych B (2001) The disposition and metabolism of tetrabromobisphenol-A after a single i.p. dose in the rat. Chemosphere 45:693–700. https://doi.org/10.1016/S0045-6535(01)00015-7
Terasaki M, Kosaka K, Kunikane S, Makino M, Shiraishi F (2011) Assessment of thyroid hormone activity of halogenated bisphenol A using a yeast two-hybrid assay. Chemosphere 84:1527–1530. https://doi.org/10.1016/j.chemosphere.2011.04.045
Wang W, Abualnaja KO, Asimakopoulos AG, Covaci A, Gevao B, Johnson-Restrepo B, Kumosani TA, Malarvannan G, Minh TB, Moon HB, Nakata H, Sinha RK, Kannan K (2015) A comparative assessment of human exposure to tetrabromobisphenol A and eight bisphenols including bisphenol A via indoor dust ingestion in twelve countries. Environ Int 83:183–191. https://doi.org/10.1016/j.envint.2015.06.015
Yang R, Liu S, Liang X, Yin N, Jiang L, Zhang Y, Faiola F (2021) TBBPA, TBBPS, and TCBPA disrupt hESC hepatic differentiation and promote the proliferation of differentiated cells partly via up-regulation of the FGF10 signaling pathway. J Hazard Mater 401:123341. https://doi.org/10.1016/j.jhazmat.2020.123341
Ye G, Chen Y, Wang HO, Ye T, Lin Y, Huang Q, Chi Y, Dong S (2016) Metabolomics approach reveals metabolic disorders and potential biomarkers associated with the developmental toxicity of tetrabromobisphenol A and tetrachlorobisphenol A. Sci Rep 6:35257. https://doi.org/10.1038/srep35257
Yin N, Liang S, Liang S, Yang R, Hu B, Qin Z, Liu A, Faiola F (2018) TBBPA and its alternatives disturb the early stages of neural development by interfering with the NOTCH and WNT pathways. Environ Sci Technol 52:5459–5468. https://doi.org/10.1021/acs.est.8b00414
Zalko D, Prouillac C, Riu A, Perdu E, Dolo L, Jouanin I, Canlet C, Debrauwer L, Cravedi JP (2006) Biotransformation of the flame retardant tetrabromo-bisphenol A by human and rat sub-cellular liver fractions. Chemosphere 64:318–327. https://doi.org/10.1016/j.chemosphere.2005.12.053
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This work was supported in part by a Grant-in-Aid for Scientific Research (23K09659) from the Japan Society for the Promotion of Science.
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Hanioka, N., Isobe, T., Saito, K. et al. Hepatic glucuronidation of tetrabromobisphenol A and tetrachlorobisphenol A: interspecies differences in humans and laboratory animals and responsible UDP-glucuronosyltransferase isoforms in humans. Arch Toxicol 98, 837–848 (2024). https://doi.org/10.1007/s00204-023-03659-1
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DOI: https://doi.org/10.1007/s00204-023-03659-1