S. Billeclke et al., Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters, DRUG META D, 28(11), 2000, pp. 1335-1342
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.