Role of Linoleic Acid Hydroperoxide Preformed by Cyclooxygenase-1 or -2 on the Regulation of Prostaglandin Formation from Arachidonic Acid by the Respective Enzyme

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Abstract

Linoleic acid (LA) preincubated with cyclooxygenase (COX)-1 or -2 inhibited prostaglandin (PG) formation from arachidonic acid (AA) catalyzed by the respective enzyme, but LA without the preincubation did not. 13 S-Hydroperoxy-9 Z,11 E-octadecadienoic acid (13-HPODE) a hydroperoxy adduct of LA inhibited PG formation catalyzed by COX-1 or -2. 13 S-Hydroxy-9 Z,11 E-octadecadienoic acid had no effect on both COX-1 and -2 activities. These results suggest that 13-HPODE which is preformed from LA by COX reaction under normal physiological conditions can be a basal suppressor of PG formation from AA.

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Most cited references 21

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Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition.

Daniel L Simmons, Regina M Botting, Timothy Hla (2004)

Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most highly utilized classes of pharmaceutical agents in medicine. All NSAIDs act through inhibiting prostaglandin synthesis, a catalytic activity possessed by two distinct cyclooxygenase (COX) isozymes encoded by separate genes. The discovery of COX-2 launched a new era in NSAID pharmacology, resulting in the synthesis, marketing, and widespread use of COX-2 selective drugs. These pharmaceutical agents have quickly become established as important therapeutic medications with potentially fewer side effects than traditional NSAIDs. Additionally, characterization of the two COX isozymes is allowing the discrimination of the roles each play in physiological processes such as homeostatic maintenance of the gastrointestinal tract, renal function, blood clotting, embryonic implantation, parturition, pain, and fever. Of particular importance has been the investigation of COX-1 and -2 isozymic functions in cancer, dysregulation of inflammation, and Alzheimer's disease. More recently, additional heterogeneity in COX-related proteins has been described, with the finding of variants of COX-1 and COX-2 enzymes. These variants may function in tissue-specific physiological and pathophysiological processes and may represent important new targets for drug therapy.

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Cox-2 inhibitory effects of naturally occurring and modified fatty acids.

T Ringbom, U Huss, A Stenholm … (2001)

In the search for new cyclooxygenase-2 (COX-2) selective inhibitors, the inhibitory effects of naturally occurring fatty acids and some of their structural derivatives on COX-2-catalyzed prostaglandin biosynthesis were investigated. Among these fatty acids, linoleic acid (LA), alpha-linolenic acid (alpha-LNA), myristic acid, and palmitic acid were isolated from a CH(2)Cl(2) extract of the plant Plantago major by bioassay-guided fractionation. Inhibitory effects of other natural, structurally related fatty acids were also investigated: stearic acid, oleic acid, pentadecanoic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Further, the inhibitory effects of these compounds on COX-2- and COX-1-catalyzed prostaglandin biosynthesis was compared with the inhibition of some synthesized analogues of EPA and DHA with ether or thioether functions. The most potent COX-2-catalyzed prostaglandin biosynthesis inhibitor was all-(Z)-5-thia-8,11,14,17-eicosatetraenoic acid (2), followed by EPA, DHA, alpha-LNA, LA, (7E,11Z,14Z,17Z)-5-thiaeicosa-7,11,14,17-tetraenoic acid, all-(Z)-3-thia-6,9,12,15-octadecatetraenoic acid, and (5E,9Z,12Z,15Z,18Z)-3-oxaheneicosa-5,9,12,15,18-pentaenoic acid, with IC(50) values ranging from 3.9 to180 microM. The modified compound 2 and alpha-LNA were most selective toward COX-2, with COX-2/COX-1 ratios of 0.2 and 0.1, respectively. This study shows that several of the natural fatty acids as well as all of the semisynthetic thioether-containing fatty acids inhibited COX-2-catalyzed prostaglandin biosynthesis, where alpha-LNA and compound 2 showed selectivity toward COX-2.

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NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro.

I Arai, Tomio Takahashi, Wayne M. Yokoyama … (1993)

NS-398 is a novel anti-inflammatory and analgesic agent which produces much fewer gastrointestinal lesions in rats. Recently, two forms of cyclooxygenase have been identified: a COX-1 first purified from ram seminal vesicles and a newly discovered mitogen-inducible form (COX-2). Effects of NS-398 on activities of these two distinct forms of COX were investigated. COX-1 purified from ram seminal vesicles and COX-2 isolated from sheep placenta (purity was 70%) were used. The COX-1 activity was completely unaffected by 10(-4) M NS-398, whereas the COX-2 activity was concentration-dependently inhibited, the IC50 value being 3.8 x 10(-6) M. Indomethacin inhibited both COX-1 and COX-2 activity to the same degree, the IC50 values being 7.4 x 10(-7) M and 9.7 x 10(-7) M, respectively. The anti-inflammatory and analgesic effects of NS-398 were almost as potent as indomethacin, the effective dose range being 0.3 approximately 5 mg/kg in rats. The gastrointestinal lesions related to NS-398 were not significant following a dose of 1000 mg/kg given orally. NS-398 is the first documented agent to have selective inhibition for COX-2, which may result in the less gastrointestinal toxicity.

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Author and article information

Journal

Journal ID (nlm-ta): J Clin Biochem Nutr

Journal ID (publisher-id): JCBN

Title: Journal of Clinical Biochemistry and Nutrition

Publisher: the Society for Free Radical Research Japan (Kyoto, Japan )

ISSN (Print): 0912-0009

ISSN (Electronic): 1880-5086

Publication date (Print): September 2008

Publication date (Electronic): 30 August 2008

Volume: 43

Issue: 2

Pages: 65-68

Affiliations

[1]Department of Physiological Chemistry, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan

Author notes

*To whom correspondence should be addressed. Tel: +81-726-90-1055 Fax: +81-726-90-1005 E-mail: fujimoto@ 123456gly.oups.ac.jp

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Publisher ID: jcbn2008047

DOI: 10.3164/jcbn.2008047

PMC ID: 2533720

PubMed ID: 18818754

SO-VID: b35c379e-7fad-47e5-9af1-b02c7e74c84b

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This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Role of Linoleic Acid Hydroperoxide Preformed by Cyclooxygenase-1 or -2 on the Regulation of Prostaglandin Formation from Arachidonic Acid by the Respective Enzyme

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Most cited references 21

Cyclooxygenase isozymes: the biology of prostaglandin synthesis and inhibition.

Cox-2 inhibitory effects of naturally occurring and modified fatty acids.

NS-398, a new anti-inflammatory agent, selectively inhibits prostaglandin G/H synthase/cyclooxygenase (COX-2) activity in vitro.

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