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.
De Costa
K S
KS
Center for Bioorganic Chemistry, Research Triangle Institute, P.O. Box 12194, 3040 Cornwallis Rd., RTP, NC 27709, USA. ksd@rti.org
Black
S R
SR
Thomas
B F
BF
Burgess
J P
JP
Mathews
J M
JM
D000818:Animals; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D051381:Rats; D011916:Rats, Inbred F344; D013343:Styrenes / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D014018:Tissue Distribution
D013343:Styrenes; C027142:vinyltoluene