Epoxide hydrolases induction

Emphasis is given to the critical role of metabolism, both detoxication and activation, in determining toxicity. The principal enzymes involved are described, including monooxygenases, esterases, epoxide hydrolases, glutathione-5 -transferases, and glucuronyl transferases. Attention is given to the influence of enzyme induction and enzyme inhibition on toxicity. 

Parkinson, A., Thomas, P.E., Ryan, D.E. etal. (1983) Differential time course of induction of rat liver microsomal cytochrome P 450 isozymes and epoxide hydrolase by Aroclor 1254. Archives of Biochemistry and Biophysics, 225, 203-215. 

It is noteworthy that, in contrast to mammalian systems, the majority of bacterial strains exhibited sufficient activity even when the cells were grown under non-optimized conditions. Since enzyme induction is still a largely empirical task, cells were grown on standard media in the absence of inducers. Furthermore, all attempts to induce epoxide hydrolase activity in Pseudomonas aeruginosa NCIMB 9571 and Pseudomonas oleovorans ATCC 29347 by growing the cells on an alkane (decane) or alkene (1-octene) as the sole carbon source failed [27]. 

Thomas H, Timms CW, Oesch F. Epoxide hydrolases molecular properties, induction, polymorphisms and function. In Ruckpaul K, Rein H, eds. Frontiers of Bio transformation. Vol. II. Principles, Mechanisms and Biological Consequences of Induction. London Taylor Francis, 1990. 

Although first reported with the cytochrome(s) P-450 mixed function oxidases, it is now known that a number of the enzymes involved in the metabolism of foreign compounds are inducible. Thus, as well as the CYPs, NADPH cytochrome P-450 reductase, cytochrome b5, glucuronosyl transferases, epoxide hydrolases, and GSTs are also induced to various degrees. However, this discussion concentrates on the induction of the CYPs with mention of other enzymes where appropriate. 

As well as detoxication via reaction with GSH, the reactive 3,4-epoxide can be removed by hydration to form the dihydrodiol, a reaction that is catalyzed by epoxide hydrolase (also known as epoxide hydratase). This enzyme is induced by pretreatment of animals with the polycyclic hydrocarbon 3-methylcholanthrene, as can be seen from the increased excretion of 4-bromophenyldihydrodiol (Table 7.5). This induction of a detoxication pathway offers a partial explanation for the decreased hepatotoxicity of bromobenzene observed in such animals. A further explanation, also apparent from the urinary metabolites, is the induction of the form of cytochrome P-450 that catalyzes the formation of the 2,3-epoxide. This potentially reactive metabolite readily rearranges to 2-bromophenol, and hence there is increased excretion of 2-bromophenol in these pretreated animals (Table 7.5). 

Gill SS, Kaur S. 1987. Hepatic epoxide hydrolase activities and their induction by clofibrate and dicthylhcxylphthalatc in various strains ofmice. Biochem Pharmacol 36 4221-4227. 

A number of inhibitors of this enzyme are known. They include epoxides that are hydrolyzed by the enzymes, such as trichloropropene oxide, metal ions such as Hg2+, Zn2+, and Cd2+ and 2-bromo-4 -acetophenone, a potent inhibitor that binds to imidazole nitrogen atoms. Microsomal epoxide hydrolase can be induced by compounds such asphenobarbital, Arochlor 1254,2(3)-t-butyl-4-hydroxyanisole (BHA), and 3,5-di-f-butyl-hydroxytoluene (BHT). Many microsomal epoxide hydrolase inducers are inducers also of CYP and produce a general proliferation of the endoplasmic reticulum. Induction does, however, involve an increase in the mRNA specific for the hydrolase. 

The importance of the cytochrome P450 monooxygenases, glutathione S-transferases, car-boxylesterases, and epoxide hydrolases in insecticide metabolism and detoxification, as well as in insecticide resistance, is well documented. It is, therefore, logical to expect that an increase in these enzyme activities resulting from induction by xenobiotics would decrease the toxicity of an insecticide because of enhanced metabolism (see review by Yu, 1986a). 

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... 

Thomas PE, Reik LM, Ryan DE, Levin W. 1981. Regulation of three forms of cytochrome P450 and epoxide hydrolase in rat liver microsomes Effects of age, sex, and induction. J. Biol. Chem. 256 1044-52... 

Induction of Hepatic CYPl A Oxygenases and Phase II Enzymes. PCBs induce hepatic Phase I enzymes (CYP oxygenases) and Phase II enzymes (e.g., UDP glucuronyltransferases, epoxide hydrolase, or glutathione transferase) to varying degrees and specificities (Connor et al. 1995 Hansen 1998 Safe... 

Andersson, T., M. Pesonen, and C. Johansson. 1985. Differential induction of cytochrome P-450-dependent monoxygenase, epoxide hydrolase, glutathione transferase and UDP glucuronyltransferase activities in the liver of the rainbow trout by 3-naphthoflavone or Clophen A50. Biochem. Pharmacol. 34 3309-3314. 

Dermal treatment of healthy volunteers with 10% coal tar for 4 days produced an 18-fold induction of CYP1A1 mRNA levels in coal-tar-treated skin (Li et al. 1995). In vitro incubation of DNA with coal tar fume concentrates in the presence of mouse and yeast microsomes expressing various cytochrome P450 isoforms or the aryl hydrocarbon hydroxylase receptor (AHR) demonstrated that coal tar fume condensates require metabolic activation to produce DNA adducts (Genevois et al. 1998). Both the AHR and CYP1A were involved in the metabolism of coal tar fume condensate. It was also shown that the reactive metabolites formed by CYP1A are substrates for microsomal epoxide hydrolase. 

DePierre, J. W., Seidegard, J., Morgenstern, R., Balk, L., Meijer, J., Astrom, A., Norelius, I., and Ernster, L. (1984) Induction of cytosolic glutathione transferase and microsomal epoxide hydrolase activities in extrahepatic organs of the rat by phenobarbi-tal, 3-methylcholanthrene and trans-stilbene oxide. Xenobiotica 14, 295-301. 

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