Functional UDP-glucuronyltransferase 2B15 polymorphism and bisphenol A concentrations in blood: results from physiologically based kinetic modelling

• Published in: Archives of toxicology Vol. 87; no. 7; pp. 1257 - 1264
• Main Authors: Partosch, Falko, Mielke, Hans, Gundert-Remy, Ursula
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2013; Springer Nature B.V
• Subjects: Area Under Curve; Benzhydryl Compounds - blood; Benzhydryl Compounds - pharmacokinetics; Biological Availability; Biomedical and Life Sciences; Biomedicine; Biotransformation; Bisphenol A; Blood; Endocrine Disruptors - blood; Endocrine Disruptors - pharmacokinetics; Environmental Health; Enzymes; Genotype; Glucuronosyltransferase - genetics; Glucuronosyltransferase - metabolism; Half-Life; Humans; Metabolic Clearance Rate; Metabolism; Models, Biological; Occupational Medicine/Industrial Medicine; Pharmacogenetics; Pharmacology/Toxicology; Phenols - blood; Phenols - pharmacokinetics; Phenotype; Polymorphism; Polymorphism, Genetic; Risk Assessment; Toxicokinetics and Metabolism; Toxicology; Bisphenol A; Physiologically based kinetic modelling; Systemic availability; Risk assessment; Polymorphically expressed UGT2B15 metabolism; Internal exposure
• ISSN: 0340-5761; 1432-0738; 1432-0738
• DOI: 10.1007/s00204-013-1022-8

Bisphenol A (BPA) is a chemical in widespread use that is under scientific discussion due to its endocrine activity. Controversies exist about how to interpret reportedly high blood concentrations measured in uncontrolled situations. Physiologically based pharmaco-/toxicokinetic modelling resulted in 10–100-fold lower blood concentrations than those reported. Moreover, in controlled situations, BPA did not exceed the level of detection (<0.3 ng/ml) in human blood or urine. Using a validated human PBK model, this study investigated the influence of functionally relevant polymorphic UGT2B15, the enzyme mediating BPA metabolism, on the BPA concentration–time profile in human blood. Maximum concentrations ( C max ) and areas under the curves (AUCs) in blood from high and low metabolisers differed by a factor of 4.7 and 4.6, respectively (doses: 1 and 0.05 μg/kg/day). Low metabolisers excreted a greater proportion of BPA via the sulphate pathway compared to high metabolisers. This finding explains why C max and AUC increased to a smaller extent, as predicted from in vitro data obtained with transfected cells possessing only the UGT2B15 variants. The highest C max value calculated in the subject with the lowest metabolic clearance was roughly 40 pg/ml, which is far lower than reported high blood concentrations, which in turn cannot be explained by genetically impaired UGT2B15 activity. From the risk assessment perspective, our results indicate that the traditional uncertainty factor is sufficient to account for the variability in the polymorphic glucuronidation of BPA.