Biotransformation of diethenylbenzenes. I. Identification of the main urinary metabolites of 1,4-diethenylbenzene in the rat.

1. Biotransformation of 1,4-diethenylbenzene (1) in rat was studied. Six urinary metabolites, namely, N-acetyl-S-[2-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine (3), N-acetyl-S-[1-(4-ethenylphenyl)-2-hydroxyethyl]-L-cysteine (4), N-acetyl-S-[1-(4-formylphenyl)-2-hydroxyethyl]-L-cysteine (5), 1-(4-ethenylphenyl)ethane-1,2-diol (6), 4-ethenylbenzoic acid (9) and 4-ethenylbenzoyl-glycine (12) were isolated and identified by n.m.r. and mass spectrometry. 2. G.l.c.-mass spectral analysis of the methylated urine extract allowed the identification of four other metabolites, as 4-ethenylphenylacetic acid (11), 4-ethenylphenylacetylglycine (13), 4-ethenylmandelic acid (7), and 4-ethenylphenylglyoxylic acid (8). 3. The structures of the identified metabolites indicate that the main reactive intermediate in the metabolism of 1 is 4-ethenylphenyloxirane (2). The first step in the biotransformation of 1, formation of an oxirane, is very similar to the metabolic activation of styrene. However, subsequent steps lead not only to analogues of styrene metabolites but also to oxidation of the second ethenyl group leading to compound(s) which may contribute to the toxicity of 1, e.g. to the aldehyde 5. 4. Rats dosed with a single i.p. dose of 1 excreted nearly 5.6% of the dose as the glycine conjugate 12, irrespective of the dose. 5. In contrast, the total thioether fraction decreased significantly with increasing dose, being 23 +/- 3, 17 +/- 5 and 12 +/- 1% of dose at 100, 200 and 300 mg/kg, respectively (mean +/- SD).