The main source of the eicosanoids is arachidonic acid. Arachidonic acid is metabolized by cyclooxygenase (COX), which initiates the synthesis of prostaglandins and thromboxanes or by lipoxygenase (LOX), which initiates the synthesis of leukotrienes (Rang et al., 1999). COX exists in two forms—COX-1 and COX-2. The structures of COX-1 and COX-2 are similar, with one amino acid difference that leads to a larger substrate access for COX-2 (Funk, 2002). COX-1 is found in most cells as a constitutive enzyme, and it is thought that the prostanoids, which it produces, are involved in normal homeostasis, for example, regulation of vascular responses. COX-2 is induced in inflammatory cells by inflammatory stimuli. On the other hand, (LOX) is present in tissues in inflammatory conditions (Rang et al., 1999).
Gingerols have been shown to inhibit arachidonic acid—induced platelet release and aggregation via an effect on the cyclooxygenase activity in platelets (Koo et al., 2001). Further, gingerols were found to have an effect on both COX-1 and COX-2 (Crowe, 2001). Ginger constituents, (8)-paradol and shogaol, showed strong inhibitory effects on COX-2 enzyme activity (Tjendraputra, 2001). Steamed ginger increases the intestinal blood flow in normal rat (Hashimoto et al., 2002). These results support the findings of the inhibitory effect on mouse mesenteric veins by steamed ginger extracts and by shogaol.
The potentiation of PGF2a-induced contraction by (±)-(6)-gingerol is present in both the normal and diabetic state to the same extent, suggesting the activation of COX-1 by gingerol. The inhibition of cyclooxygenase activity by gingerols in platelets (Koo et al., 2001) and in arthritic conditions (Sharma et al., 1994) may be related to its inhibition of COX-2. Increased vascular permeability in the diabetic state reflects the effects of COX-2—derived PGs and LTs (Funk, 2002). The stimulatory effect of gingerol on COX-
1 and the increase in production of prostanoids that will regulate the vascular function may counteract the effects of COX-2— and LOX-derived mediators in inflammatory conditions and in diabetes. However, the specific effect of gingerol on COX-1 and COX-
2 requires further investigation using selective COX-2 inhibitors; for example, Coxibs (Funk, 2002).
On the other hand, shogaol has been reported to have strong inhibitory effects on COX-2. When the structure of (8)-shogaol is compared to (8)-paradol, as well as two synthetic analogues, 3-hydroxy-1-(4-hydroxy-3-methoxyphenyl) decane and 5-hydroxy-1-(4-hydroxy-3-methoxyphenyl) dodecane, three important structural features that affect COX-2 inhibition are revealed: (1) lipophilicity of the alkyl side chain, (2) substitution pattern of hydroxy and carbonyl groups on the side chain, and (3) substitution pattern of hydroxy and methoxy groups on the aromatic moiety (Tjendraputra et al., 2001).
The chemical structures of gingerols and shogaols have a different moiety in the side chain. The aliphatic hydroxyl group in gingerol is necessary for the potentiation of PGF2a-induced contractions in mice mesenteric veins (Kimura et al., 1989c). Elimination of the hydroxyl group (e.g., in the shogaol structure) inhibited the contractile response to PGF2a.These findings suggest that the hydroxyl group in gingerol affects the activation of the cyclooxygenase in mice mesenteric vein (Kimura et al., 1989c; Pancho et al., 1989). The different effects of gingerol (a main component of fresh ginger) and shogaol (a main component of steamed ginger) on COX-1 and COX-2 suggest that the combination of the two drugs may be used as an effective treatment for diabetes mellitus and other inflammatory conditions. See Chapter 14 for other pharmacological effects and medicinal uses of ginger.
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