A comprehensive investigation into the effect of bisphenol A on the expression of drug-metabolizing enzymes: Consequences for endogenous metabolites and xenobiotic pharmacokinetics.

Bisphenol A, a known endocrine disruptor, is a pervasive environmental contaminant because of its widespread use in everyday consumer products. It has been linked to numerous health hazards and shown to modulate the drug-metabolizing enzymes. There is a significant disparity in reported results in the literature, chiefly because of a focus on mRNA expression or substrate activity assays rather than on protein expression. The present study uses mass spectrometry-based targeted proteomics to investigate modulation in the expression of drug-metabolizing enzymes following environmentally relevant exposure to bisphenol A in a rat model. Furthermore, the plasma levels of endogenous metabolites of cytochrome P450 (CYP) 1B1, the highest fold-modulated enzyme, were also monitored. The pharmacokinetics of diclofenac, a substrate of the CYP2C family and UDP-glucuronosyltransferase (UGT) 2B7, were also studied. We identified 9 significantly altered proteins in hepatic drug metabolism, with 4 upregulated (CYP1B1, CYP1A2, UGT2B7, and UGT1A3) and 5 downregulated (CYP2A3, CYP2C13, CYP4A2, and UGT2B1). The upregulation of CYP1B1 leads to increased levels of endogenous metabolites, including retinoic acid and 4-hydroxyestradiol, which are teratogenic and procarcinogenic, respectively. The upregulation of UGT2B7 led to increased exposure to the acyl-glucuronide metabolite of diclofenac, which is known to cause hepatotoxicity, intestinal ulceration, and nephrotoxicity. SIGNIFICANCE STATEMENT: This study uses a mass spectrometry-based targeted proteomics approach to monitor all relevant drug-metabolizing enzymes (DMEs) after exposure to bisphenol A in a rat model. The study presents protein-level data of relevant DMEs and identified 9 significantly altered DMEs in hepatic drug metabolism. The modulation of DMEs is reflected in alterations in numerous endogenous metabolite levels with plausible adverse consequences. Further, the pharmacokinetics of substrate xenobiotic modulated by these enzymes is also altered.