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1.
Drug Metab Dispos ; 27(12): 1423-8, 1999 Dec.
Article in English | MEDLINE | ID: mdl-10570023

ABSTRACT

The induction of benoxaprofen (BNX) glucuronidation in rats by intragastric administration of three nitrogen heterocycles (quinoline, 2,2'-dipyridyl, or 1,7-phenanthroline at 75 mg/kg daily for 3 days) has been investigated. BNX was administered i.v. at a dose of 20 mg/kg to bile-cannulated rats that had been induced. Blood and bile were collected over 8 h. Liver tissues were also collected at the end of the 8-h study and used to examine conjugation activity of BNX by UDP-glucuronosyl transferases and cytochrome P-450 enzyme activities in vitro. Two methods were used to characterize the true metabolic formation rates of the labile benoxaprofen glucuronide conjugate in vitro, which gave comparable mean values for K(M) and V(max). There appeared to be a trend of increase of the V(max) of BNX glucuronidation in rat liver microsomes by all three nitrogen heterocycles; however, the induction was only significant with 1,7-phenanthroline. K(M) was not noticeably altered by any of the three inducers. No change of measured hepatic microsomal cytochrome P-450 activities in the rat was found. BNX glucuronidation in rats in vivo was increased by all three nitrogen heterocycles with 1,7-phenanthroline more effective than quinoline and 2,2'-dipyridyl. The use of nitrogen heterocycles provides a means to modulate exposure to labile, reactive acyl glucuronides in vivo without apparent changes in oxidative metabolism.


Subject(s)
2,2'-Dipyridyl/pharmacology , Anti-Inflammatory Agents, Non-Steroidal/metabolism , Glucuronates/metabolism , Phenanthrolines/pharmacology , Propionates/metabolism , Quinolines/pharmacology , Administration, Oral , Animals , Cytochrome P-450 Enzyme System/biosynthesis , Drug Interactions , Enzyme Induction , Glucuronic Acid/metabolism , Glucuronosyltransferase/biosynthesis , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Rats , Rats, Sprague-Dawley
2.
Toxicol Sci ; 44(1): 14-21, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9720136

ABSTRACT

The disposition of oral doses of [14C]benzene was investigated using a range of doses that included lower levels (0.02 and 0.1 mg/kg) than have been studied previously in rat, mouse, and in hamster, a species which has not been previously examined for its capacity to metabolize benzene. Saturation of metabolism of benzene was apparent as the dose increased, and a considerable percentage of the highest doses (100 mg/kg) was exhaled unchanged. Most of the remainder of the radioactivity was excreted as metabolites in urine, and significant metabolite-specific changes occurred as a function of dose and species. Phenyl sulfate was the predominant metabolite in rat urine at all dose levels (64-73% of urinary radioactivity), followed by prephenlmercapturic acid (10-11%). Phenyl sulfate (24-32%) and hydroquinone glucuronide (27-29%) were the predominant metabolites formed by mice. Mice produced considerably more muconic acid (15%), which is derived from the toxic metabolite muconaldehyde, than did rats (7%) at a dose of 0.1 mg/kg. Unlike both rats and mice, hydroquinone glucuronide (24-29%) and muconic acid (19-31%) were the primary urinary metabolites formed by hamsters. Two metabolites not previously detected in the urine of rats or mice after single doses, 1,2,4-trihydroxybenzene and catechol sulfate, were found in hamster urine. These data indicate the hamsters metabolize benzene to more highly oxidized, toxic products than do rats or mice.


Subject(s)
Benzene/pharmacokinetics , Animals , Benzene/administration & dosage , Biotransformation , Chromatography, High Pressure Liquid , Cricetinae , Feces/chemistry , Male , Mice , Mice, Inbred Strains , Rats , Rats, Inbred F344 , Species Specificity , Spectrophotometry, Ultraviolet
3.
Chem Res Toxicol ; 11(7): 778-85, 1998 Jul.
Article in English | MEDLINE | ID: mdl-9671540

ABSTRACT

The effect of trans-1,2-dichloroethylene (DCE), an inhibitor of cytochrome P450 (P450) 2E1, on the catalytic activities and total content of hepatic P450 was determined in vivo and in vitro. Hepatic microsomes were prepared from groups of rats prior to dosing and at 2, 5, 12, and 24 h postdosing, and total P450 content and the activities of P450 1A2, P450 2A1, P450 2B, P450 2C6, P450 2C11, P450 2D1, P450 2E1, and P450 3A were determined. The lowest dose of DCE that yielded maximal inactivation of P450 2E1 was found to be 100 mg/kg. Significant decreases in total content of P450 or the activities of P450 1A2, P450 2A1, P450 2B, P450 2C6, P450 2C11, P450 2D1, and P450 3A were not observed during the 24 h following administration of DCE (100 mg/kg ip), but P450 2E1 activity was diminished about 65% at 2 and 5 h after DCE treatment and returned to control levels at 24 h. Additionally, there was little or no significant effect on the activities of hepatic cytosolic alcohol dehydrogenase or mitochondrial or microsomal aldehyde dehydrogenases 5 h postdosing. DCE showed the same selectivity for P450 inactivation in vitro, and P450 2E1 activity was inhibited by >80% without affecting the other isozymes. However, DCE (5 mM) also proved to be a good competitive inhibitor of the probe activities of P450 1A2 and P450 2C6. The in vivo inhibition of P450 2E1 was accompanied by decreases in the levels of the immunoreactive protein, and an additional immunoreactive band appeared at ca. 30 kDa in the Western blot of microsomes from DCE-treated rats, possibly arising from proteolytic degradation of P450 2E1 protein after covalent modification by the inhibitor. DCE is an effective, relatively nontoxic inhibitor of P450 2E1 in vivo and in vitro that has greater selectivity than other agents currently used.


Subject(s)
Cytochrome P-450 CYP2E1 Inhibitors , Dichloroethylenes/pharmacology , Enzyme Inhibitors/pharmacology , Alcohol Dehydrogenase/metabolism , Aldehyde Dehydrogenase/metabolism , Animals , Blotting, Western , Cytosol/drug effects , Cytosol/enzymology , Electrophoresis, Polyacrylamide Gel , In Vitro Techniques , Male , Mitochondria, Liver/drug effects , Mitochondria, Liver/enzymology , Rats , Rats, Inbred F344
4.
Toxicol Appl Pharmacol ; 146(2): 255-60, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9344893

ABSTRACT

The effect of trans-1,2-dichloroethylene (DCE), an inhibitor of cytochrome P450 (P450) 2E1 (CYP2E1), on the composition and quantity of volatile organic chemicals (VOCs) expired in the breath of male F-344 rats was determined in parallel with hepatic P450 activity and content. Hepatic microsomes were prepared from groups of rats prior to dosing and at 2, 5, 12, and 24 hr postdosing with DCE (100 mg/kg ip), and total P450 content and the activity of CYP2E1 was determined. Breath was collected from parallel groups of rats predose and at several intervals that encompassed the time points for rats euthanized for microsome preparation. Over 100 breath components were identified by GC/MS and quantitated by GC/FID. The overall change in the profile of breath VOCs resulting from administration of DCE was striking. An increase of approximately 1000% was measured in the mass of non-DCE-derived VOCs exhaled 4-6 hr after dosing, but there was no increase in hepatic lipid peroxidation. In addition to hexane, short-chain methyl ketones were particularly affected, and percentage increases in response to inhibition were inversely related to chain length, with acetone and 2-butanone > 2-pentanone >> 2-hexanone > 2-heptanone. There were no statistically significant decreases in total content of P450, but the activity of CYP2E1 was diminished about 65% at 2 and 5 hr after DCE treatment. However, 24 hr after inhibitor administration the total mass of VOCs expired was only marginally elevated above baseline and CYP2E1 activity was not significantly different from that of untreated rats. The compounds most markedly increased upon inhibition of CYP2E1 are also excellent inducers of that isozyme, and this finding is consistent with the hypothesis that these chemicals are important to the normal homeostasis of CYP2E1. The increase in breath components observed following inhibition of CYP2E1 suggests that VOCs in breath can reflect the activity of that isozyme in vivo.


Subject(s)
Breath Tests , Cytochrome P-450 CYP2E1 Inhibitors , Cytochrome P-450 CYP2E1/analysis , Dichloroethylenes/toxicity , Hydrocarbons/analysis , Ketones/analysis , Microsomes, Liver/enzymology , Acetone/analysis , Animals , Butanones/analysis , Cytochrome P-450 CYP2E1/metabolism , Dichloroethylenes/administration & dosage , Gas Chromatography-Mass Spectrometry , Hexanes/analysis , Injections, Intraperitoneal , Lipid Peroxidation/drug effects , Male , Methylation , Microsomes, Liver/drug effects , Pentanones/analysis , Rats , Rats, Inbred F344 , Substrate Specificity , Volatilization
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