REGULATION OF THE FUNCTION AND EXPRESSION OF HUMAN ALDEHYDE OXIDASE

Abstract

Aldehyde oxidase (AOX) has emerged as an important drug-metabolizing enzyme because of its increased role in drug metabolism and toxicity. Herein, this study is focused on factors affecting AOX activity either through inhibition or transcriptional regulation. By comparing various selective estrogen receptor modulators (SERMs) and their structural analogues/metabolites, we found that SERMs differentially inhibit AOX activity and identified structural features of bazedoxifene and lasofoxifene that contribute to AOX inhibition.In addition, we identified the first two nuclear receptors, pregnane X receptor (PXR) and retinoid X receptor (RXR), that play a role in the regulation of AOX expression. Agonists of both nuclear receptors induce AOX mRNA and protein levels in human cell models, as determined by real-time PCR and our newly-developed quantitative targeted proteomics method. In conclusion, our findings provide new insights into the potential interactions between SERMs, PXR and RXR modulators and AOX substrates (drugs and endogenous chemicals).