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Evaluation of bisphenol A glucuronidation according to UGT1A1*28 polymorphism by a new LC-MS/MS assay
Trdan Lušin, Tina (Author), Roškar, Robert (Author), Mrhar, Aleš (Author)

URLURL - Presentation file, Visit http://www.sciencedirect.com/science/article/pii/S0300483X11004987 This link opens in a new window

Abstract
The endocrine disruptor bisphenol A (BPA) is a frequently used chemical in the manufacture of consumer products. In humans, BPA is extensively metabolised to BPA glucuronide (BPAG) by different UDP-glucuronosyltransferase (UGT) isoforms. The study has been performed with the intention to improve the accuracy of published physiologically-based pharmacokinetic models and to improve regulatory risk assessments of BPA. In order to gain insight into intestine, kidney, liver, and lung glucuronidation of BPA, human microsomes of all tested organs were used. BPAG formation followed Michaelis-Menten kinetics in the intestine and kidney, but followed substrate inhibition kinetics in the liver. Human lung microsomes did not show glucuronidation activity towards BPA. While the liver intrinsic clearance was very high (857 mL min-1 kg body weight-1), the tissue intrinsic clearances for the kidney and intestine were less than 1% of liver intrinsic clearance. Since BPA is a UGT1A1 substrate, we postulated that the common UGT1A1*28 polymorphism influences BPA glucuronidation, and consequently, BPA detoxification. Hepatic tissue intrinsic clearances for UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*28 microsomes were 1113, 1075, and 284 mL min-1 kg body weight-1, respectively. Prior to microsomal experiments, the bioproduction of BPAG and stable isotope-labeled BPAG (BPAGd16) was performed for the purpose of the reliable and accurate quantification of BPAG. In addition, a sensitive LCMS/ MS analytical method for the simultaneous determination of BPA and BPAG based on two stable isotope-labeled internal standards was developed and validated. In conclusion, our in vitro results show that the liver is the main site of BPA glucuronidation (Km 8.9 ìM, Vmax 8.5 nmol min-1 mg-1) and BPA metabolism may be significantly influenced by a personćs genotype (Km 10.0 - 13.1 ìM, Vmax 3.4 - 16.2 nmol min-1 mg-1). This discovery may be an important fact for the currently on-going worldwide BPA risk assessments and for the improvement of physiologically-based pharmacokinetic models.

Language:English
Keywords:bisfenol A, mikrosomi, masna spektrometrija, tekočinska kromatografija, UDP glukuronoziltransferaza
Work type:Not categorized (r6)
Tipology:1.01 - Original Scientific Article
Organization:FFA - Faculty of Pharmacy
Year:2012
Number of pages:str. 33-41
Numbering:Vol. 292, iss. 1
UDC:577:615.9
ISSN on article:0300-483X
DOI:10.1016/j.tox.2011.11.015 Link is opened in a new window
COBISS.SI-ID:3168369 Link is opened in a new window
Views:1026
Downloads:239
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Record is a part of a journal

Title:Toxicology
Shortened title:Toxicology
Publisher:North-Holland Publishing
ISSN:0300-483X
COBISS.SI-ID:26540544 This link opens in a new window

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