In vivo metabolism of isomeric naphthalene oxide glutathione conjugates.
We have examined the fate of glutathione conjugates derived from naphthalene metabolism at various dose levels (5-80 mg/kg) in an effort to explore the potential use of urinary mercapturic acids as biomarkers of exposure to naphthalene and as indicators of the activity and stereoselectivity of cytochrome P-450-dependent naphthalene epoxidation. This approach extends previous studies which demonstrated a high degree of stereoselectivity in the formation of (+)-1R,2S-naphthalene oxide from naphthalene in target tissue microsomes (mouse lung), but not in microsomal preparations isolated from nontarget tissues such as mouse liver. To validate the use of mercapturic acids as indicators of epoxide formation in vivo, individual naphthalene oxide glutathione adduct isomers were administered iv to mice, and urinary metabolites were identified and quantified. Mercapturates accounted for 69-75% of the administered dose in the 8-hr urines of animals treated with trans-1-(S)-hydroxy-2-(S)-glutathionyl-1,2-dihydronaphthalene (adduct 1) and 76-84% for trans-1-(R)-hydroxy-2-(R)-glutathionyl-1,2-dihydronaphthalene (adduct 2). Only 39-57% of the dose of trans-1-(R)-glutathionyl-2-(R)-hydroxy-1,2-dihydronaphthalene (adduct 3) administered to mice was excreted as the mercapturic acid derivative; however, two additional metabolites were detected which were not present in the urine of animals treated with adducts 1 or 2. The first metabolite, accounting for 2-4% of the dose of adduct 3, was not identified. The second metabolite, isolated by HPLC and identified by mass spectrometry as (hydroxy-1,2-dihydronaphthalenylthio)pyruvic acid, accounted for 14-25% of the administered dose of adduct 3.(ABSTRACT TRUNCATED AT 250 WORDS)
Buonarati
M
M
Department of Pharmacology and Toxicology, School of Veterinary Medicine, University of California, Davis 95616.
Jones
A D
AD
Buckpitt
A
A
D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D003545:Cysteine / Q000378:metabolism; D004151:Dipeptides / Q000378:metabolism; D005243:Feces / Q000032:analysis; D005260:Female; D005978:Glutathione / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D009281:Naphthalenes / Q000378:metabolism*; D013237:Stereoisomerism
D004151:Dipeptides; D009281:Naphthalenes; C042033:naphthalene 1,2-oxide; C028505:cysteinylglycine; D005978:Glutathione; D003545:Cysteine; D000111:Acetylcysteine