Correlations of the induction of microsomal epoxide hydrolase activity with phase II drug conjugating enzyme activities in rat liver.
Within the selective induction of phase II enzymes following treatment with dipyridyls or N-heterocyclic analogs of phenanthrene, strong correlations (r > or = 0.70) are observed between the increase of microsomal epoxide hydrolase (mEH) activity and UDP-glucuronosyltransferase (UGT) activities towards 4-nitrophenol, 1-naphthol and morphine. The present study investigates whether this correlation is maintained with inducing agents known to also increase phase I enzyme activities. Rats were treated with beta-naphthoflavone, isosafrole, phenobarbital, ethanol, dexamethasone and clofibric acid regimens in which P450 isozyme induction could be confirmed. Comparisons between the responses of mEH, UGT and glutathione S-transferase (GST) activities were made. mEH activity was increased by beta-naphthoflavone, isosafrole, phenobarbital and clofibric acid. The elevation in mEH activity by these agents showed modest but significant correlations with GST activities toward all the substrates monitored (r values range between 0.49 and 0.65) and a strong correlation with UGT activity towards only one substrate, morphine (r = 0.70). This study suggests that induction of mEH activity correlates with the increases in select phase II enzyme activities whether it is accompanied by P450 induction or not.
Slawson
M H
MH
Department of Pharmacology and Toxicology, University of Utah, Salt Lake City 84112, USA.
Franklin
M R
MR
Moody
D E
DE
D000818:Animals; D001571:Benzoflavones / Q000494:pharmacology; D002995:Clofibric Acid / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction; D004851:Epoxide Hydrolases / Q000096:biosynthesis*; D000431:Ethanol / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000096:biosynthesis; D005982:Glutathione Transferase / Q000096:biosynthesis; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D010088:Oxidoreductases / Q000096:biosynthesis; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012451:Safrole / Q000494:pharmacology; D019324:beta-Naphthoflavone
D001571:Benzoflavones; D000431:Ethanol; D002995:Clofibric Acid; D019324:beta-Naphthoflavone; D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D014453:Glucuronosyltransferase; D005982:Glutathione Transferase; D004851:Epoxide Hydrolases; D012451:Safrole; C015959:isosafrole; D010634:Phenobarbital