Abstract
It is well established that human serum paraoxonase (PON1) catalyzes the hydrolysis 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 and cyclic carbonate esters. The lactone substrates vary in their ring size from 4 to 7 atoms. Substituents on the ring carbons may enhance or reduce the rate of lactone hydrolysis. An appreciable degree of stereospecificity exists with some activities differing up to 9-fold between enantiomers (i.e.,S-α-hydroxy-γ-butyrolactone is hydrolyzed 5 to 9 times faster than the R form). Thiolactones are hydrolyzed less efficiently, and some lactams are potent inhibitors. Four lactone-containing drugs—spironolactone, mevastatin, 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 by the Q than R isozyme, whereas others show a reverse preference. Moreover, these new substrates include homogentisic acid lactone, mevalonic acid lactone, homocysteine thiolactone, and γ-hydroxybutyric acid lactone—all lactone forms of endogenous compounds. It is reasonable to expect that further 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 and cyclic carbonate ester substrates and compare these properties with those of representative arylesters and organophosphates.
Footnotes
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Send reprint requests to: Dr. Bert N. La Du, M.D., Ph.D., Department of Pharmacology, University of Michigan Medical School, MSRB 3, Room 1301, Ann Arbor, MI 48109-0632. E-mail:bladu{at}umich.edu
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This work was presented in part at the Experimental Biology 99 meeting, Washington, DC, April, 1999.
- Abbreviations used are::
- PON1
- paraoxonase
- LDL
- low density lipoprotein
- HTL
- homocysteine thiolactone
- PC
- phosphatidyl choline
- Received April 8, 2000.
- Accepted July 25, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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