Metabolism and disposition of alpha-methylstyrene in rats.

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.

Reduction of 1,3-diphenyl-1-triazene by rat hepatic microsomes, by cecal microflora, and in rats generates the phenyl radical metabolite: nn ESR spin-trapping investigation.

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.

Absorption, metabolism, and disposition of 1,3-diphenyl-1-triazene in rats and mice after oral, i.v., and dermal administration.

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 (