The effect of pyridine on the in vitro and in vivo metabolism of ethyl carbamate (urethane) by rat and mouse.
Ethyl carbamate (EC, urethane) is a known carcinogen in laboratory animals. A genotoxic mechanism has been proposed which involves the bioactivation of EC to a reactive epoxide by the ethanol-inducible CYP2E1. The purpose of this study was to determine if pyridine (200 mg/kg i.p.), an inducer of CYP2E1, would increase the in vitro metabolism of EC and the in vivo binding of EC to cellular macromolecules. Treatment of rats or mice with pyridine increased hepatic microsomal metabolism of [14C-carbonyl]EC to CO2, but had little effect on pulmonary microsomal metabolism. The increase in hepatic metabolism was inhibited by the CYP2E1 inhibitor diethyldithiocarbamate, but not by the esterase inhibitor paraoxon, clearly indicating a role for this isozyme in hepatic metabolism of EC. In vivo, pyridine (200 mg/kg i.p.) administered 18 h prior to dosing with EC decreased the binding of [14C-ethyl]EC to cellular macromolecules. These data indicate that pyridine administration to rats and mice induces CYP2E1 metabolism of EC in vitro, but inhibits EC metabolism in vivo, perhaps by acting as an alternate substrate for CYP2E1.
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Department of Pharmacology and Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, IN 47907.
Carlson
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D000818:Animals; D019392:Cytochrome P-450 CYP2E1; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004247:DNA / Q000378:metabolism; D004050:Ditiocarb / Q000494:pharmacology; D004790:Enzyme Induction; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D018632:Mice, Inbred SENCAR; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D010261:Paraoxon / Q000494:pharmacology; D011506:Proteins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D012313:RNA / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D014520:Urethane / Q000378:metabolism*
D065607:Cytochrome P-450 Enzyme Inhibitors; D011506:Proteins; D011725:Pyridines; D014520:Urethane; D012313:RNA; D004247:DNA; D003577:Cytochrome P-450 Enzyme System; D004050:Ditiocarb; D019392:Cytochrome P-450 CYP2E1; D010089:Oxidoreductases, N-Demethylating; C023666:pyridine; D010261:Paraoxon