Biotransformation of styrene in mice. Stereochemical aspects

Biotransformation of styrene and its toxic metabolite, phenyloxirane (1), i n mice in vivo was studied. Mice were treated with. single intraperitoneal doses of styrene (400 mg/kg of body weight), and with (R)-, (S)-, or racemi c styrene oxide (150 mg/kg of body weight). Profiles of neutral and acidic metabolites were determined by GC/MS. Mandelic acid (3) and two mercapturic acids, N-acetyl-S-(2-hydroxy-2-phenylethyl)cysteine (5) and N-acetyl- S-(2 -hydroxyl-phenylethyl)cysteine (6), were found to be major urinary metaboli tes of bath. styrene and phenyloxirane. 1-Phenylethane-1,2-diol (2) was the main neutral metabolite, The rate of excretion of this metabolite, as dete rmined by GC; was 5-10 times lower than that of mandelic acid. Several mino r acidic metabolites were also identified. Among them, novel phenolic metab olites, namely, 2-(4-hydroxyphenyl)ethanol (7), (4-hydroxyphenyl)acetic aci d (11), and two isomeric hydroxymandelic acids (12), are of toxicological s ignificance. Main stereogenic metabolites were isolated as methyl esters fr om extracts of pooled acidified urine treated with diazomethane. The mandel ic acid that was obtained was converted to diastereomeric Mosher's derivati ves prior to analysis by NMR. Mercapturic acids were analyzed directly: by C-13 NMR, Pure enantiomers of 1 were metabolized predominantly but not excl usively to corresponding enantiomers of 3. Styrene yielded predominantly (S )-mandelic acid. Fractions of mercapturic acids 5 and 6 isolated from urine amounted to 12-15% of the dose for all compounds that were administered. C onversion to mercapturic acids was highly regio and stereoselective, yieldi ng predominantly regioisomer 5. Styrene, as compared to racemic phenyloxira ne, yielded slightly more diastereomers arising from (S)-1 than from (R)-1. These data can be explained by formation of a moderate excess of the less mutagenic (S)-1 in the metabolic activation of styrene in mice in vivo.