I. Linhart et al., BIOTRANSFORMATION OF DIETHENYLBENZENES .5. IDENTIFICATION OF URINARY METABOLITES OF 1,2-DIETHENYLBENZENE IN THE RAT, Xenobiotica, 26(12), 1996, pp. 1263-1272
1. Biotransformation of 1,2-diethenylbenzene (1) in rat was studied. F
ive urinary metabolites were isolated by extraction of acid hydrolysed
urine and identified by nmr and mass spectroscopy, namely, 1-(2-ethen
ylphenyl)ethane-1,2-diol (2) 2-ethenylmandelic acid (3), 2-ethenylphen
ylglyoxylic acid (4), 2-ethenylphenylacetylglycine (5) tyl-S-[1-(2-eth
enylphenyl)-2-hydroxyethyl]cysteine (6) and yl-S-[2-(2-ethenylphenyl)-
2-hydroxy-ethyl]cysteine (7). 2. In addition, minor metabolites, namel
y, 2-ethenylbenzoic acid (8) and 2-ethenylphenyl-acetic acid (9) were
identified by glc-mass spectral analysis of the hydrolysed urine extra
ct treated subsequently with diazomethane, hydroxylamine and a trimeth
yl-silylating reagent. Several compounds, which could arise from biotr
ansformation of both ethenyl groups in the molecule of 1, were detecte
d but not identified unequivocally. 3. A glucuronide was detected by t
ie analysis of urine as a blue spot after spraying with naphthoresorci
nol. Compounds showing molecular fragments indicating the glucuronide
moiety were also detected by glc-mass spectroscopy in non-hydrolysed u
rine samples. 4. The total thioether excretion amounted to 5.3 +/- 2.4
, 5.1 +/- 3.4 and 5.0 +/- 1.9% of the dose at 500, 300 and 100 mg/kg,
respectively (mean +/- SD; n = 5). 5. Like styrene and other diethenyl
benzene isomers, 1,2-diethenylbenzene is metabolically activated to a
reactive epoxide intermediate, 2-ethenylphenyloxirane (10), which is f
urther converted to the urinary metabolites mentioned above. The main
detoxification pathways are hydrolysis to the glycol 2 followed by sev
eral oxidation steps, and conjugation with glutathione. The latter rea
ction is both regioselective and stereoselective. 6. The ratio of merc
apturic acids 6:7 was 83:17. Each regioisomer consists of two diastere
omers which show distinct resonance signals in the C-13-nmr. The diast
ereomer ratio was 82:28 and 79:21 for 6 and 7 respectively.