Differential induction of cytosolic eposide hydrolase, microsomal epoxide hydrolase, and glutathione S-transferase activities

Bruce D. Hammock, Kenji Ota

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120 Scopus citations


Three major enzyme systems have been shown to metabolize epozidized xenobiotics in vertebrate tissues, and this study demonstrates that these enzyme systems can be differentially induced. The cytosolic epoxide hydrolase activity was routinely monitored with trans-β-ethylstyrene oxide, the microsomal epoxide hydrolase activity with benzo(a)pyrene, 4,5-oxide, and the glutathione S-transferase activity with 2,4-dichloro-4-nitrobenzene. Commonly used inducers of microsomal mixed-function oxidase, microsomal epoxide hydrolase, and cytosolic glutathione S-transferase activities failed to cause significant induction of the cytosolic epoxide hydrolase while leading to the expected induction of the other epoxide metabolizing enzymes. The compounds tested by ip injection into male Swiss-Webster mice included phenobarbital, 3-methylcholanthrene, Arochlor 1254, trans- and cis-stilbene oxides, pregnenolone-16α-carbonitrile, chalcone, and 4-bromochalcone. To determine if there were strain, sex, or species differences, the enzymes were monitored in male C57BL/6 mice, female Swiss-Webster mice, and male Sprague-Dawley rats following ip injection of phenobarbital, 3-methylcholanthrene, and/or pregnenolone-16α-carbonitrile. The time dependence of enzyme induction was followed in Sprague-Dawley rats following trans-stilbene oxide administration. Male Swiss-Webster mice were additionally exposed to dietary α-naphthoflavone and 2(3)-tert-butyl-4-hydroxyanisole while male Sprague-Dawley rats were fed 2,6-di-tert-butyl-4-methylphenol. In no case was significant induction of cytosolic epoxide hydrolase activity observed. Dietary di-(2-ethylhexyl)phthalate, 2-ethyl-1-hexanol, and clofibrate proved to be potent inducers of the cytosolic epoxide hydrolase in male Swiss-Webster mice while probucol (a nonperoxisome proliferating hypolipidemic drug) failed to cause significant induction. Data from isoelectric focusing experiments and other data are consistent with the epoxide hydrolase activities induced by 2-ethyl-1-hexanol and clofibrate being due to the same protein that is present in control animals. The lack of induction of the cytosolic epoxide hydrolase by a variety of compounds which were selected to demonstrate induction of other xenobiotic metabolizing enzymes, may indicate that the cytosolic epoxide hydrolase has a constitutive role whereas its induction by clofibrate could be related to some of the pharmacological and/or carcinogenic actions of this drug.

Original languageEnglish (US)
Pages (from-to)254-265
Number of pages12
JournalToxicology and Applied Pharmacology
Issue number2
StatePublished - 1983

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology


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