Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters

It is well established that human serum paraoxonase (PON1) catalyzes the hy drolysis of organophosphate insecticides and nerve agents, as well as that of a number of aromatic carboxylic acid esters. Our laboratory has recently found a new class of PON1 substrates that includes at least 30 lactones an d cyclic carbonate esters. The lactone substrates vary in their ring size f rom 4 to 7 atoms. Substituents on the ring carbons may enhance or reduce th e rate of lactone hydrolysis. An appreciable degree of stereospecificity ex ists with some activities differing up to 9-fold between enantiomers (i.e., S-alpha-hydroxy-gamma-butyrolactone is hydrolyzed 5 to 9 times faster than the R form). Thiolactones are hydrolyzed less efficiently, and some lactam s are potent inhibitors. Four lactone-containing drugs-spironolactone, meva statin, simvastatin, and lovastatin-have been identified as substrates for PON1. All lactone substrates are hydrolyzed by both the Q and R isozymes of human serum PON1. However, some lactone substrates are hydrolyzed faster b y the Q than R isozyme, whereas others show a reverse preference. Moreover, these new substrates include homogentisic acid lactone, mevalonic acid lac tone, homocysteine thiolactone, and gamma-hydroxybutyric acid lactone-all l actone forms of endogenous compounds. It is reasonable to expect that furth er investigations may uncover PON1 lactone substrates that are, themselves, endogenous compounds. In this article we characterize the basic enzymatic properties of PON1's newly identified hydrolytic activities with lactone an d cyclic carbonate ester substrates and compare these properties with those of representative arylesters and organophosphates.