Stereochemical aspects of styrene biotransformation.
Urine of rats dosed with styrene (240 mg/kg), R-, S- and racemic styrene oxide (150 mg/kg) was analysed for mandelic acid enantiomers and for regioisomers and diastereomers of mercapturic acids by NMR spectrometry. Enantiomers of mandelic acid were converted to diastereomeric Mosher's derivatives prior to analysis. R- and S-styrene oxide yielded predominantly R- and S-mandelic acid, respectively, racemic styrene oxide gave predominantly the R-enantiomer whereas styrene yielded almost racemic mandelate. The regioselectivity of mercapturic acid formation was very similar for styrene, R- and S-styrene oxide. These three species yielded a 2:1 mixture of N-acetyl-S-(1-phenyl-2-hydroxyethyl)cysteine (MA1) and N-acetyl-S-(2-phenyl-2-hydroxyethyl)cysteine (MA2). R-Styrene oxide gave higher conversion to mercapturic acids (28%) than the S-isomer (19% of the dose). However, R-styrene oxide yielded stereospecifically S,R-MA1 and R,R-MA2 whereas S-styrene oxide gave R,R-MA1 and S,R-MA2. Styrene yielded a mixture of diastereomeric mercapturic acids. The ratios of R,R-/S,R-isomers were 80:20 and 15:85 for MA1 and MA2, respectively. These data suggest that styrene is metabolised stereoselectively to S-styrene oxide as a major enantiomer in rat in vivo. This enantiomer has been reported to be less mutagenic than R-styrene oxide in vitro.
Linhart
I
I
Prague Institute of Chemical Technology, Department of Organic Chemistry, Czech Republic. igor.linhart@vscht.cz
Smejkal
J
J
Mládková
I
I
D000111:Acetylcysteine / Q000737:chemistry / Q000652:urine; D000818:Animals; D001711:Biotransformation; D004852:Epoxy Compounds / Q000737:chemistry / Q000493:pharmacokinetics / Q000652:urine; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008333:Mandelic Acids / Q000737:chemistry / Q000652:urine; D009153:Mutagens / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D020058:Styrene; D013343:Styrenes / Q000737:chemistry / Q000493:pharmacokinetics* / Q000652:urine
D004852:Epoxy Compounds; D008333:Mandelic Acids; D009153:Mutagens; D013343:Styrenes; D020058:Styrene; C013690:styrene oxide; C037938:mandelic acid; D000111:Acetylcysteine