Billecke S, Draganov D, Counsell R, Stetson P, Watson C, Hsu C, La Du B N
Department of Anesthesiology and Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan 48109-0632, USA.
Drug Metab Dispos. 2000 Nov;28(11):1335-42.
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-alpha-hydroxy-gamma-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 gamma-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.
众所周知，人血清对氧磷酶（PON1）可催化有机磷杀虫剂和神经毒剂的水解，以及多种芳香族羧酸酯的水解。我们实验室最近发现了一类新的PON1底物，其中至少包括30种内酯和环状碳酸酯。内酯底物的环大小从4到7个原子不等。环碳上的取代基可能会提高或降低内酯水解的速率。存在明显程度的立体特异性，一些活性在对映体之间相差高达9倍（即S-α-羟基-γ-丁内酯的水解速度比R型快5至9倍）。硫内酯的水解效率较低，一些内酰胺是有效的抑制剂。已确定四种含内酯的药物——螺内酯、美伐他汀、辛伐他汀和洛伐他汀——为PON1的底物。所有内酯底物都可被人血清PON1的Q和R同工酶水解。然而，一些内酯底物被Q同工酶水解的速度比R同工酶快，而另一些则表现出相反的偏好。此外，这些新底物包括尿黑酸内酯、甲羟戊酸内酯、同型半胱氨酸硫内酯和γ-羟基丁酸内酯——所有这些都是内源性化合物的内酯形式。可以合理预期，进一步的研究可能会发现本身就是内源性化合物的PON1内酯底物。在本文中，我们描述了PON1新确定的内酯和环状碳酸酯底物水解活性的基本酶学性质，并将这些性质与代表性芳基酯和有机磷酸酯的性质进行了比较。
