title: Biotransformation of the double bond in allyl glycidyl ether to an epoxide ring. Evidence from hemoglobin adducts in mice.
abstract: Allyl glycidyl ether (AGE) is used industrially in the production of various epoxy resins. The compound is mutagenic and evidence for carcinogenicity in mice and rats has been reported. A previous study in mice showed that AGE reacts directly, without metabolic activation, with N-terminal valine in hemoglobin to form adducts (AGEVal). Metabolism of AGE may lead to formation of diglycidyl ether (I) through epoxidation of the double bond or 1-allyloxy-2,3-dihydroxypropane (II) through hydrolysis of the epoxide ring. 2,3-Dihydroxypropyl glycidyl ether (III) may be formed either by hydrolysis of I or epoxidation of II. The main aim of the present study was to investigate if AGE is metabolized to the reactive epoxides I or III by analysis of adducts with hemoglobin. Nine male mice (C3H/Hej) were administered AGE dissolved in tricaprylin, 4 mg/mouse, by intraperitoneal (i.p.) injection. Eleven male mice were administered 4 mg/mouse of AGE dissolved in acetone, by skin application. Adducts of I or III with N-terminal valine, N-(2-hydroxy-3-(2,3-dihydroxy)propyloxy)propylvaline (diOHPrGEVal), were demonstrated in mice administered AGE by i.p. injection. The levels were in the range 1600-5600 pmol/g globin. The level of diOHPrGEVal in mice administered AGE by skin application (n = 5) was below the detection limit of the analytical method, 20 pmol/g globin. The level of AGEVal, analyzed in mice administered AGE by skin application (n = 6), was about 20 pmol/g globin (median value), as compared with 1600 pmol/g globin previously found in mice administered AGE by i.p. injection. Neither AGEVal nor diOHPrGEVal were detected in control animals. Both adducts were analyzed using a modified Edman method for derivatization and using gas chromatography/tandem mass spectrometry for detection. The hydroxyl groups of the Edman derivative of diOHPrGEVal were protected by acetylation.
authors.affiliation: Department of Molecular Genome Research, Stockholm University, Sweden. hermes.licea_perez@molgen.su.se
authors.forename: H L
authors.initials: HL
authors.lastname: Pérez
authors.forename: S
authors.initials: S
authors.lastname: Osterman-Golkar
mesh_terms: D000818:Animals; D001711:Biotransformation; D004852:Epoxy Compounds / Q000493:pharmacokinetics*; D008401:Gas Chromatography-Mass Spectrometry; D006454:Hemoglobins / Q000378:metabolism*; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D014633:Valine / Q000378:metabolism
chemical_list: D004852:Epoxy Compounds; D006454:Hemoglobins; C054361:allyl glycidyl ether; D014633:Valine