Epoxide metabolism in the liver of mice treated with clofibrate (ethyl-α-(p-chlorophenoxyisobutyrate)), a peroxisome proliferator

David E. Moody, Dana N. Loury, Bruce D. Hammock

Research output: Contribution to journalArticle

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Abstract

An increase in cytosolic epoxide hydrolase (cEH) activity occurs in the livers of mice treated with peroxisome proliferating-hypolipidemic-nongenotoxic carcinogens. As increases in activity of epoxide metabolizing enzymes may reflect the carcinogenic mechanism, a detailed comparison of the response of cEH, microsomal epoxide hydrolase (mEH), and cytosolic glutathione S-transferase (cGST) activities using the geometrical isomers trans- and cis-stilbene oxide as substrates has been performed in livers from mice treated with clofibrate (ethyl-α-(p-chlorophenoxyisobutyrate)). The maximal increase of cEH activity occurred at lower dietary doses of clofibrate (0.5%) and within a shorter time (5 days) than mEH and cGST (2%, 14 days) activity. After 14 days at 0.5% clofibrate, cEH, mEH, and cGST activities were 250, 175, and 165% and 290, 220, and 75% of control values in male and female mice, respectively. Withdrawal of clofibrate from the diet resulted in a reversion of activities to control values within 7 days. Clofibrate treatment shifted the apparent subcellular compartmentation of all three enzymatic activities with an increase in the ratio of soluble to particulate activity. In particular, the relative specific activity of all three enzymes decreased in the light mitochondrial (peroxisomal) cell fraction, and an increase of a mEH-like activity (benzo[a]pyrene-4,5-oxide and cis-stilbene oxide hydrolysis) in the cytosol occurred. Both the increase of cEH activity and the appearance of mEH-like activity in the cytosol are novel responses of epoxide metabolizing enzymes, which may be related to the novel cellular responses that follow clofibrate treatment, peroxisome proliferation, hypolipidemia, and nongenotoxic carcinogenesis.

Original languageEnglish (US)
Pages (from-to)351-362
Number of pages12
JournalToxicology and Applied Pharmacology
Volume78
Issue number3
DOIs
StatePublished - 1985

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Clofibric Acid
Peroxisome Proliferators
Epoxide Hydrolases
Clofibrate
Epoxy Compounds
Metabolism
Liver
Glutathione Transferase
Hydrolases
Peroxisomes
Enzymes
Cytosol
Nutrition
Isomers
Carcinogens
Hydrolysis
Carcinogenesis

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Epoxide metabolism in the liver of mice treated with clofibrate (ethyl-α-(p-chlorophenoxyisobutyrate)), a peroxisome proliferator. / Moody, David E.; Loury, Dana N.; Hammock, Bruce D.

In: Toxicology and Applied Pharmacology, Vol. 78, No. 3, 1985, p. 351-362.

Research output: Contribution to journalArticle

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abstract = "An increase in cytosolic epoxide hydrolase (cEH) activity occurs in the livers of mice treated with peroxisome proliferating-hypolipidemic-nongenotoxic carcinogens. As increases in activity of epoxide metabolizing enzymes may reflect the carcinogenic mechanism, a detailed comparison of the response of cEH, microsomal epoxide hydrolase (mEH), and cytosolic glutathione S-transferase (cGST) activities using the geometrical isomers trans- and cis-stilbene oxide as substrates has been performed in livers from mice treated with clofibrate (ethyl-α-(p-chlorophenoxyisobutyrate)). The maximal increase of cEH activity occurred at lower dietary doses of clofibrate (0.5{\%}) and within a shorter time (5 days) than mEH and cGST (2{\%}, 14 days) activity. After 14 days at 0.5{\%} clofibrate, cEH, mEH, and cGST activities were 250, 175, and 165{\%} and 290, 220, and 75{\%} of control values in male and female mice, respectively. Withdrawal of clofibrate from the diet resulted in a reversion of activities to control values within 7 days. Clofibrate treatment shifted the apparent subcellular compartmentation of all three enzymatic activities with an increase in the ratio of soluble to particulate activity. In particular, the relative specific activity of all three enzymes decreased in the light mitochondrial (peroxisomal) cell fraction, and an increase of a mEH-like activity (benzo[a]pyrene-4,5-oxide and cis-stilbene oxide hydrolysis) in the cytosol occurred. Both the increase of cEH activity and the appearance of mEH-like activity in the cytosol are novel responses of epoxide metabolizing enzymes, which may be related to the novel cellular responses that follow clofibrate treatment, peroxisome proliferation, hypolipidemia, and nongenotoxic carcinogenesis.",
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