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Editorials

Paraoxonase and Coronary Heart Disease Risk

Language Misleads, Linkage Misinforms, Function Clarifies

Joseph Loscalzo, MD, PhD

From the Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass.

Correspondence to Joseph Loscalzo, MD, PhD, Department of Medicine, Brigham and Women’s Hospital, 75 Francis St, Boston, MA 02115. E-mail jloscalzo@partners.org

Key Words: Editorials • genes

An extract of the first 250 words of the full text is provided, because this article has no abstract.

Organophosphates were first synthesized in the 1930s as insecticides¹ and were subsequently shown to have direct neurotoxic effects in mammals, as well. The neurotoxicity is derived from their ability to inhibit acetylcholinesterase by covalently modifying the active-site serine group in the enzyme. Mazur² first demonstrated the presence of an organophosphate-hydrolyzing enzyme in mammalian tissue, an observation that ultimately led to the identification of a human paraoxonase in serum in 1953.³ Paraoxonase—so named because of its ability to hydrolyze the toxic metabolite of parathion, paraoxon—was also shown early after its identification to manifest arylesterase activity, an effect that was underappreciated until the enzyme was found to play a role in modulating vascular oxidant stress many years later.

Article see p 147

The paraoxonase story is a good example of the power of language to mislead. There is no teleological reason for mammals to have evolved an enzyme that can hydrolyze synthetic organophosphates; yet, paraoxonase was isolated in an effort to understand the endogenous metabolism of these exogenous neurotoxins. The enzymatic activity for which the enzyme is named is screened by using synthetic substrates without regard for the native substrate or its role in human (patho)biology. This focus on one aspect of the enzyme’s function, overemphasized by its denotation, delayed an appreciation of other potential—and perhaps more relevant—roles. In 1991, Mackness et al⁴ showed that paraoxonase could limit the accumulation of lipid hydroperoxides in low-density lipoprotein, thereby ushering in an era of interest in its relationship to atheroprotection. Although the preferred endogenous . . . [Full Text of this Article]

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