RESUMO
1,3-Diphenyl-1-triazene (DPT) is used in the synthesis of polymers and dyes, and has been found as an impurity in the color additives D&C Red 33 and FD&C Yellow 5. [(14)C]DPT, randomly labeled in the phenyl rings, was used to investigate its disposition in rodents. Dermal doses to rats and mice (2 and 20 mg/cm(2)) were poorly absorbed (=7%) in 72 h of exposure. Oral doses of DPT (20 mg/kg) to male rats and mice were well absorbed and excreted mainly in the urine, with exhalation of volatile organics accounting for about 1% of the dose. The sole volatile component present in breath was benzene, and all of the metabolites present in urine were composed of those known for the differential metabolism of benzene and for aniline in the two species. Benzene and aniline were detected in the blood of rats administered oral doses of DPT, and relatively high circulating levels of their metabolites were measured as early as 15 min postdosing. Metabolites of these two carcinogens were also formed in human liver slices, indicating a carcinogenic potential for DPT in humans.
Assuntos
Aditivos Alimentares/farmacocinética , Triazenos/farmacocinética , Administração Cutânea , Administração Oral , Animais , Feminino , Aditivos Alimentares/metabolismo , Humanos , Técnicas In Vitro , Injeções Intravenosas , Fígado/metabolismo , Taxa de Depuração Metabólica , Camundongos , Ratos , Ratos Endogâmicos F344 , Triazenos/metabolismoRESUMO
An ESR spin-trapping technique was used to determine whether free radical metabolites are formed as a result of the reduction of 1, 3-diphenyl-1-triazene (DPT) in vivo and in vitro by components of the cytochrome P450 (P450) mixed-function oxidase system in microsomes or by gut microflora in anaerobic cecal incubations. The ESR spectrum of the DMPO-phenyl radical adduct was detected in a microsomal incubation containing DPT, DMPO, and NADPH with the following hyperfine coupling constants: a(N) = 15.95 G and = 24.37 G. The amplitude of the spectrum from the phenyl radical adduct generated in microsomal incubations of DPT with DMPO and NADPH was not attenuated by the P450 inhibitor 1-aminobenzotriazole (ABT) or by carbon monoxide, indicating that P450 is not significantly involved in phenyl radical formation. The formation of a DMPO-phenyl radical adduct was also catalyzed by recombinant human cytochrome P450 reductase. Addition of anti-rat P450 reductase antibody led to an attenuation of the signal in incubations containing either microsomes or reductase. Low concentrations of DMPO-phenyl radical adducts were detected by ESR in the toluene extract of cecal contents containing DPT and the spin trap. In the in vivo experiments with rats treated with DPT and the spin trap DMPO, the six-line ESR signal of the DMPO-phenyl radical adduct was readily detected in bile 40-60 min after rats were treated with DPT and DMPO. The results show for the first time that the phenyl radical is formed by the reduction of DPT and may indicate a toxic potential for this chemical.
Assuntos
Derivados de Benzeno/metabolismo , Ceco/metabolismo , Ceco/microbiologia , Aditivos Alimentares/metabolismo , Microssomos Hepáticos/enzimologia , Triazenos/metabolismo , Animais , Derivados de Benzeno/química , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/metabolismo , Espectroscopia de Ressonância de Spin Eletrônica/métodos , Radicais Livres/química , Radicais Livres/metabolismo , Humanos , Masculino , Oxigenases de Função Mista/metabolismo , NADPH-Ferri-Hemoproteína Redutase/metabolismo , Oxirredução , Ratos , Ratos Endogâmicos F344 , Proteínas Recombinantes/metabolismo , Marcadores de SpinRESUMO
alpha-Methylstyrene (AMS) is a volatile hydrocarbon used primarily in the production of specialty polymers and resins. In the present study, the tissue distribution, metabolism, and excretion of [(14)C]AMS was investigated in male rats after i.v. administration (11 mg/kg). Over 90% of AMS administered intravenously to rats was excreted in 72 h. Urinary excretion accounted for 86% of the administered dose, volatile breath and feces accounted for 2.2 and 1.9%, respectively, and elimination as carbon dioxide was negligible. Metabolites were isolated from rat urine following a high oral dose of AMS (1000 mg/kg) and characterized using gas chromatography/mass spectrometry and NMR spectrometry. The metabolites were 2-phenyl-1,2-propanediol (3% of urinary radioactivity) and its glucuronide (50%), atrolactic acid (27%), S-(2-hydroxy-2-phenylpropyl)-N-acetylcysteine (13%), and 2-phenylpropionic acid (1%); the glucuronides and mercapturates were each conjugated on the methylene carbon beta to the ring. The presence of both of the diastereomeric isomers of the mercapturates and of the glucuronides suggested that the initial epoxidation of AMS was not stereoselective and proceeded with addition of active oxygen to yield enantiomeric epoxides. Incubation of AMS with human liver slices produced the same metabolites as those excreted in rat urine, with 2-phenyl-1,2-propanediol present as the predominant metabolite after 5 h of incubation.