Tropolones enzyme inhibition

Hinokitiol is a tropolone type natural compound isolated from the wood of Chymacyparis taiwanesis. The compound has been utilized as a natural antimicrobial agent in hair tonics, toothpastes, cosmetics and food supplements. Hinokitiol was evaluated on five different arachidonic acid metabolic pathways for the mechanism of action of anti-inflammatory effects. It has been found to be a potent inhibitor with IC50 values of 0.1 pM against platelet-type 12-LOX and 50 pM against leukocyte-type 12-LOX. It also inhibited soybean 5-LOX enzyme (IC50 = 17 pM). However, hinokitiol had almost no effects on COX-1 and COX-2 enzymes. Similar inhibition profiles were also observed on synthetic tropolone derivatives [168]. 

Substrates of COMT include xenobiotics catechols, catecholamines, and catechol estrogens. Three functional classes of chemicals are known to inhibit COMT. S-Adenosyl-I-homocysteine (SAH) is a potent inhibitor of COMT as well as the other SAM-dependent methyltransferases. Inhibition results from SAH binding to the SAM binding site on the enzyme. Certain divalent ions such as Ca+2 and trivalent metal ions such as the salts of lanthanides, neodymium, and europium are excellent inhibitors of COMT. A number of catechol-type substrates such as pyrogallol, fla-vonoids, pyrones, pyridenes, hydroxyquiolines, 3-mercaptotyramine, and tropolones are irreversible inhibitors of COMT. 

It was argued [1256] that provided the tropolones did not act simply as metal ion scavangers (as in the case, for example, with ethylene diamine tetra-cetic acid [1258]), since chelation with metal ions undoubtedly underlies the antifungal properties [1259, 1260] of the thujaplicins and their congeners, then they should be able to compete with the catecholamines for the active enzymic site. The results showed that some of the tropolones, including the two thujaplicins, did in fact act in this way. Presumably the inhibition [1261] of dopamine jS-hydroxylase by y-thujaplicin occurs by a similar mechanism. 

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