Inhibitory effects of fifteen phthalate esters in human cDNA-expressed UDP-glucuronosyltransferase supersomes

Abstract

Phthalate esters (PAEs) have been extensively used in industry as plasticizers and there remains concerns about their safety. The present study aimed to determine the inhibition of phthalate esters (PAEs) on the activity of the phase II drug-metabolizing enzymes UDP-glucuronosyltransferases (UGTs). In vitro recombinant UGTs-catalyzed glucuronidation of 4-methylumbelliferone was used to investigate the inhibition potentials of PAEs towards various s UGTs. PAEs exhibited no significant inhibition of UGT1A1, UGT1A3, UGT1A8, UGT1A10, UGT2B15, and UGT2B17, and limited inhibition of UGT1A6, UGT1A7 and UGT2B4. However, UGT1A9 was strongly inhibited by PAEs. In silico docking demonstrated a significant contribution of hydrogen bonds and hydrophobic interactions contributing to the inhibition of UGT by PAEs. The K values were 15.5, 52.3, 23.6, 12.2, 5.61, 2.79, 1.07, 22.8, 0.84, 73.7, 4.51, 1.74, 0.58, 6.79, 4.93, 6.73, and 7.23 μM for BBOP-UGT1A6, BBZP-UGT1A6, BBOP-UGT1A7, BBZP-UGT1A7, DiPP-UGT1A9, DiBP-UGT1A9, DCHP-UGT1A9, DBP-UGT1A9, BBZP-UGT1A9, BBOP-UGT1A9, DMEP-UGT1A9, DPP-UGT1A9, DHP-UGT1A9, DiBP-UGT2B4, DBP-UGT2B4, DAP-UGT2B4, and BBZP-UGT2B4, respectively. In conclusion, exposure to PAEs might influence the metabolic elimination of endogenous compounds and xenobiotics through inhibiting UGTs.

Structurally Optimized Fluorinated Small‐Sized Graphene Oxide for Enhanced Magnetic Resonance Imaging during Pregnancy

“…The zebrafish serves as a cost‐effective and highly prolific in vivo toxicity test model, with a short reproductive cycle and easy observability. [ 56‐59 ] Notably, the 86.6% homology between zebrafish and human genes implies that experimental findings may have significant implications for human health. [ 60 ]…”

Medical devices as a source of phthalate exposure: a review of current knowledge and alternative solutions

“…Two studies of how phthalates affect drug-metabolising uridine 5’-diphospho-glucuronosyltransferases (UGTs) ( 45 , 46 ) confirmed limited inhibition of some recombinant human UGTs and possible interference with the metabolism of various endogenous and xenobiotic substances. Since UGT isoforms have a key role in metabolism of xenobiotics, this interference should be taken into account for patients exposed to phthalates.…”