In vitro inhibition effect of various pharmacologically relevant drugs on recombinant paraoxonase 1

Paraoxonase-1 (PON1) is a metalloenzyme associated with high-density lipoproteins (HDL), and as such, it is present in the mammalian bloodstream. It is believed that PON1 is involved in the oxidative-stress-related pathophysiological processes of several diseases. Although serum PON1 activity and concentration have potential as disease biomarkers, many drugs can also modulate its activity, thereby potentially compromising its diagnostic utility. Therefore, we screened the National Medical Products Administration-approved drug library of 1409 compounds to identify relatively potent inhibitors of recombinant PON1 (rePON1). Nine pharmacologically relevant compounds exhibited inhibition constants (K_i) ranging from 10 μM to 1000 μM, while prulifloxacin and efavirenz emerged as the most potent competitive inhibitors of rePON1 with K_i values around 1 μM. Thus, these two drugs bind rePON1 approximately 2- to 3-fold more tightly than 2-hydroxyquinoline, which is the most kinetically and structurally characterized competitive inhibitor of rePON1.