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Journal ArticleDOI

A radiometric assay for hepatic epoxide hydrase activity with [7-3H] styrene oxide☆

10 Mar 1971-Biochimica et Biophysica Acta (Elsevier)-Vol. 227, Iss: 3, pp 685-691
TL;DR: The simplicity of the present assay permits the use of epoxide hydrase a a marker enzyme for microsomal membranes in hepatic microsomes increases during maturation of rats and following pretreatment of rats with phenobarbital or 3-methylcholanthrene.
About: This article is published in Biochimica et Biophysica Acta.The article was published on 1971-03-10. It has received 407 citations till now. The article focuses on the topics: Epoxide hydrolase activity & Styrene oxide.
Citations
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Journal ArticleDOI
Franz Oesch1
TL;DR: Whether a given aromatic or olefinic compound produces such an effect would depend on a variety of factors, such as the relative rate of formation and degradation of the intermediate oxirane, on its stability with respect to spontaneous isomerization to the corresponding phenol and on its chemical electrophilic reactivity.
Abstract: 1. Several aromatic and olefinic compounds are converted to intermediate arene and alkene oxides by mammalian mono-oxygenases. Intermediate arene oxides rearrange non-enzymically to phenols. Arene and alkene oxides are converted by epoxide hydrases to vicinal diols and by glutathione S-epoxide conjugases to glutathione conjugates. Due to their high electrophilic reactivity, such oxiranes also bind to proteins, RNA and DNA. Mutagenic, carcinogenic and cytotoxic effects of several aromatic and olefinic compounds appear to be due to the formation of intermediate epoxides and their reaction with tissue constituents. Whether a given aromatic or olefinic compound produces such an effect would thus depend on a variety of factors, such as the relative rate of formation and degradation of the intermediate oxirane, on its stability with respect to spontaneous isomerization to the corresponding phenol and on its chemical electrophilic reactivity.2. Epoxide hydrases, which convert such intermediate oxiranes t...

805 citations

Book ChapterDOI
TL;DR: This chapter discusses the role of intermediates such as free radicals, radical cations, and carbonium ions in polycyclic hydrocarbon carcinogenesis, and discusses the factors that can influence the formation, further metabolism, and biological effectiveness of polycyclIC hydrocarbon epoxides.
Abstract: Publisher Summary This chapter provides information on the metabolism and the biological activities of polycyclic aromatic hydrocarbons. Three types of products—dihydrodiols, glutathione conjugates, and phenols—have been found as the metabolites of aromatic hydrocarbons in tissue preparations. Oxidative metabolism at the double bonds of aromatic substrates leads to the formation of epoxides. Epoxide metabolites are responsible for many of the biological effects that have been attributed to the parent hydrocarbons. The chapter discusses the role of intermediates such as free radicals, radical cations, and carbonium ions in polycyclic hydrocarbon carcinogenesis. It also discusses the factors that can influence the formation, further metabolism, and biological effectiveness of polycyclic hydrocarbon epoxides. Epoxides may prove to be biologically important derivatives that are formed from polycyclic hydrocarbons by microsomal metabolism; alternatively, they may not. The exact molecular mechanism that leads to the initiation of malignancy by hydrocarbons remains obscure, although strong suspicions persist that somatic mutations induced by metabolites are involved.

725 citations

References
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Journal Article
TL;DR: It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for thetreatment of Cushing's syndrome.
Abstract: In increasingly large numbers, drugs, pesticides, herbicides, food additives, and environmental carcinogenic hydrocarbons are being found to stimulate their own metabolism or the metabolism of other compounds. The evidence suggests that foreign chemicals exert this action by increasing the amount of drug-metabolizing enzymes in liver microsomes.Treatment of animals or man with suitable inducers of liver microsomal enzymes accelerates drug metabolism in vivo and alters the duration and intensity of drug action. For instance, barbiturates decrease the anticoagulant activity of coumarin anticoagulants by accelerating their metabolism. This effect requires that the dosage of coumarins be raised to obtain an adequate anticoagulant response, and serious toxicity can result after combined therapy with a coumarin anticoagulant and a stimulator of drug metabolism when the enzyme stimulator is withdrawn and the anticoagulant is continued without an appropriate decrease in dose. The stimulatory effect of drugs on their own metabolism often allows the organism to detoxify drugs more rapidly. This effect has considerable importance when it causes drugs to become less toxic and less effective during prolonged administration. However, if a metabolite has more activity than the parent drug, enzyme induction can enhance the drug's action. Enzyme induction may also be important during chronic exposure to environmental carcinogens, such as 3, 4-benzpyrene. The ability of 3, 4-benzpyrene to stimulate its own metabolism in liver, lung, gastrointestinal tract and skin represents an important mechanism for the detoxification of this substance. Inducers of microsomal enzymes stimulate the metabolism or synthesis of several normal body substrates such as steroid hormones, pyridine nucleotides, cytochromes, and bilirubin. Evidence has accumulated that steroids are normal body substrates of drug-metabolizing enzymes in liver microsomes. Accordingly, treatment of rats with phenobarbital enhances the hydroxylation of androgens, estrogens, glucocorticoids, and progestational steroids by liver microsomes. This effect is paralleled in vivo by enhanced metabolism of steroids to polar metabolites and by a decreased action of steroids such as estradiol, estrone, and progesterone. Recent studies suggest that inducers of liver microsomal enzymes enhance the hydroxylation of steroids in man. Phenobarbital, diphenylhydantoin, and phenylbutazone are examples of drugs that stimulate cortisol hydroxylase activity in guinea pig liver microsomes and enhance the urinary excretion of 6 β-hydroxycortisol in man. Further research is needed to learn whether the stimulatory action of drugs on the metabolism of normal body constituents is harmful or whether it restores a homeostasis that was upset by drug administration. It is of considerable interest that certain inducers of liver microsomal enzymes have recently been used therapeutically for the treatment of hyperbilirubinemia in jaundiced children and for the treatment of Cushing's syndrome. Considerable further work is required to evaluate more completely the effects of liver microsomal enzyme inducers on the metabolism of bilirubin, cortisol, and other normal body constituents in experimental animals and man.

2,869 citations

Journal ArticleDOI
TL;DR: Phenol is a major nonenzymatic product in all enzymatic studies with benzene oxide and the enzyme, “epoxide hydrase,” is found in both the microsomal and the soluble fractions and converts a variety of epoxides to 1,2-glycols.

213 citations