Pharmacological Interactions of Paraoxonase 1 (PON1): A HDL-Bound Antiatherogenic Enzyme

Abstract

A growing interest exists in documenting the role of paraoxonase 1 (PON1) in different human diseases including, cardiovascular disease, obesity, diabetes mellitus, cancers, aging, and several neurological disorders. Three aspects of PON1 have attracted the attention of researchers: (1) hydrolyzing and detoxifying of toxic organophosphorous compounds such as nerve gases; (2) antioxidative activity in hydrolyzing oxidized phospholipids in high-density lipoprotein (HDL) and low-density lipoprotein (LDL); (3) interaction with various drugs. Drugs and nutrients which can increase the activity of paraoxonases contribute to reduce atherosclerosis and other disorders. There were contradictory reports on the interactions of PON1 with various drugs. These findings may be a reflection of differences in the dosage and type of drug, length of treatment, genetic variations, particularly loss-of-function polymorphisms, and the model used (cultured cells, animal studies or human studies). In addition, it should be noted that the regulatory effects of a drug on the enzyme protein may be important because a drug may induce the PON1 gene while having inhibitory effects on its enzymatic activity. Due to the association of PON1 with various human diseases, this review is focused on the pharmacological aspects of PON1 and the study of interactions between the enzyme and various drugs that may potentially assist to better understand the role of PON1 in drug metabolism, as well as the effects of drugs on PON1 status (activity and gene expression). In general, increasing our knowledge about the antioxidant and antiatherogenic enzyme will assist in determining efficient preventive and therapeutic strategies in the management of human disorders, particularly vascular diseases and those which are associated with negative regulation of PON1.