Inhibition of epoxidation

Epoxide metabolites can be generated from a variety of aromatic systems. Anticonvulsants are a class of drug whose side-effects, such as hepatic necrosis and aplastic anaemia, are thought to be mediated by chemically reactive epoxide metabolites formed by cytochrome P450 oxidation. For instance phenytoin (Figure 8.6) toxicity is correlated with oxidation and the inhibition of epoxide hydrolase [8]. 

In an attempt to identify the proposed epoxide intermediate of chlorobenzene, Oesch (1973) co-administered the epoxide hydrase inhibitor cyclohexane oxide together with chlorobenzene to rats. Instead of increasing the toxicity of chlorobenzene as expected, through the inhibition of epoxide hydrase, cyclohexane oxide actually decreased the metabolism of chlorobenzene and its necrotic toxicity on the liver, suggesting that the metabolism of chlorobenzene is partially responsible for its liver toxicity. 

Oesch F, Jerina DM, Daly JW, et al. 1973. Induction, activation and inhibition of epoxide hydrase An anomylous prevention of chlorobenzene - induced hepatotoxicity by an inhibitor of epoxide hydrase. Chem Biol Interact 6 189-202. 

Recently, sterically differently substituted epoxides, such as reactive metabolites of the pesticides vinclozolin, rotenone, and phenothrin, were investigated in terms of their ability to inhibit epoxide hydrolase. Mono-and di-substituted oxiranes were good substrates and strong noncompetitive inhibitors of hepatic epoxide hydrolase, whereas tri-substituted epoxides were virtually inactive in this regard (Cova et al 1986). Obviously, selective inhibition of epoxide hydrolase by epoxide metabolites could interfere with the natural protection of the organism against other toxic epoxides. 

Felbamate Carbamazepine Risk of toxicity due to concomitant rise in carbamazepine epoxide concentration and pharmacodynamic interaction Induction of carbamazepine metabolism, possible inhibition of epoxide hydrolase and pharmacodynamic interaction... 

Valnoctamide Carbamazepine Risk of carbamazepine toxicity Inhibition of epoxide hydrolase... 

Valproic acid is an enzyme inhibitor that can inhibit specific cytochrome P450 isozymes, epoxide hydrolase, and UGT isozymes. The addition of valproic acid to phenobarbital results in a 30% to 50% decrease in the clearance of phenobarbital and potential toxicity if the dose of phenobarbital is not reduced. Valproic acid may increase concentrations of 10,11-carbamazepine epoxide without affecting concentrations of the parent drug via inhibition of epoxide hydrolase. Valproic acid is also a potent inhibitor of lamotrigine, via inhibition of UGT enzymes, and can result in a doubling of the half-life of lamotrigine. ... 

An example of inhibition of phase I hydrolytic metabolism, is the inhibition of epoxide hydrolase by valpromide, which increases the levels of carbamazepine , (p.537). Phase II conjugative metabolism can also be inhibited. Examples are the inhibition of carbamazepine glucuronidation by... 

There is also some debate about whether the combination of valproate (especially valpromide) and carbamazepine should be avoided, not only because of the risk of toxicity but also because inhibition of epoxide hydrolase may be undesirable. This enzyme is possibly important for the detoxification of a number of teratogenic, mutagenic and carcinogenic epoxides. More study is needed. 

Robbins DK, Wedlund PJ, Kuhn R, Baumann RJ, Levy RH, Chang S-L. Inhibition of epoxide hydrolase by valproic acid in epileptic patients receiving carbamazepine. BrJ Clin Pharmacol (1990) 29, 759-62. 

TABLE 6. Inhibition of epoxide hydratase by metabolically produced epoxides. Styrene oxide was used as substrate. 

Methylene chloride is one of the more stable of the chlorinated hydrocarbon solvents. Its initial thermal degradation temperature is 120°C in dry air (1). This temperature decreases as the moisture content increases. The reaction produces mainly HCl with trace amounts of phosgene. Decomposition under these conditions can be inhibited by the addition of small quantities (0.0001—1.0%) of phenoHc compounds, eg, phenol, hydroquinone, -cresol, resorcinol, thymol, and 1-naphthol (2). Stabilization may also be effected by the addition of small amounts of amines (3) or a mixture of nitromethane and 1,4-dioxane. The latter diminishes attack on aluminum and inhibits kon-catalyzed reactions of methylene chloride (4). The addition of small amounts of epoxides can also inhibit aluminum reactions catalyzed by iron (5). On prolonged contact with water, methylene chloride hydrolyzes very slowly, forming HCl as the primary product. On prolonged heating with water in a sealed vessel at 140—170°C, methylene chloride yields formaldehyde and hydrochloric acid as shown by the following equation (6). 

Lee TW, Chemey MM, Huitema C, Liu J, James KE, Powers JC, Eltis LD, James MN (2005) Crystal structures of the main peptidase from the SARS coronavirus inhibited by a substrate-fike aza-peptide epoxide. J Mol Biol 353 1137-1151 Liang PH (2006) Characterization and inhibition of SARS-coronavirus main protease. Curr Top Med Chem 6 361-376... 

This is not discussed in detail since mechanisms of resistance have been carefully reviewed (Ghannoum and Rice 1999). It was pointed out that resistance has not been associated with modification of the structure. For the 1,2,4-triazoles that have been widely used, their effect is due to inhibition of the synthesis of ergosterol that is the dominant component of fungal cell membranes. Resistance is generally associated with modification of the target enzymes, for example, the epoxidation of squalene (Terbinafine) or 14a-demethylase (Fluconazole). Resistance of Candida albicans to the azole antifungal agent fluconazole demonstrated, however, the simultaneous occurrence of several types of mechanism for resistance (Perea et al. 2001) ... 

Methylated derivatives of 7-methylB[a]A are particularly carcinogenic when substitutes in the 7-, 12-, or 6- and 8-positions (152,153). The increased carcinogenicity of these compounds may result from the inhibition of metabolism at the 8-11 positions which increases the amounts of bay region diol epoxides formed, the greater reactivity of such epoxides with DNA, or an intrinsic difficulty for cells to repair such adducts (154). 

The catalyst is preliminarily oxidized to the state of the highest valence (vanadium to V5+ molybdenum to Mo6+). Only the complex of hydroperoxide with the metal in its highest valence state is catalytically active. Alcohol formed upon epoxidation is complexed with the catalyst. As a result, competitive inhibition appears, and the effective reaction rate constant, i.e., v/[olefin][ROOH], decreases in the course of the process due to the accumulation of alcohol. Water, which acts by the same mechanism, is still more efficient inhibitor. Several hypothetical variants were proposed for the detailed mechanism of epoxidation. 

Since acidity (Lewis or Brpnsted) impacts adversely on the yield of epoxides, Clerici and Ingallina (204) added basic compounds in low concentrations to TS-1 catalysts during epoxidation of alkenes to inhibit the oxirane ring opening and enhanced the epoxide yields. A comprehensive investigation of the influence of pH on product selectivity in epoxidation of allylalcohol, allylchloride, and styrene catalyzed by various titanosilicates was reported recently by Shetti et al (205). 

E. C. Dietze, J. Stephens, J. Magdalou, D. M. Bender, M. Moyer, B. Fowler, B. D. Hammock, Inhibition of Human and Murine Cytosolic Epoxide Hydrolase by Group-Selective Reagents , Comp. Biochem. Physiol., B 1993, 104, 299 - 308. 

Ghiasuddin SM, Matsumura F. 1982. Inhibition of gamma-amino butyric acid (GABA)-induced chloride uptake by gamma-BHC-d heptachlor epoxide. Comp Biochem Physiol 73C 141-144. 

Yamaguchi I, Matsumura F, KadousAA. 1979. Inhibition of synaptic ATPases by heptachlor epoxide in rat brain. Pesticide Biochemistry and Physiology 11 285-293. 

Grundy DL, Still GG, Inhibition of acetylcholinesterases by puiegone — 1,2-epoxide, Pest Biochem Physiol25 3 5—5, 1985. 

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