Stereochemical metabolism of styrene in volunteers

Abstract

Stereochemical metabolism of styrene in volunteersWenker, M.A.M.; Kezic, S.; Monster, A.C.; de Wolff, F.A. General rightsIt is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), other than for strictly personal, individual use, unless the work is under an open content license (like Creative Commons). Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Abstract Objectives: To study the stereochemistry of styrene metabolism in volunteers, and its interindividual variability. Methods: Twenty healthy male volunteers (aged 18±37 years) were exposed to 360 mg/m 3 styrene for 1 h while they performed 50 W physical exercise. Venous blood was drawn during and for up to 2 h after exposure. Urine was collected at time-intervals up to 24 h after exposure. The following parameters were determined: styrene, free and conjugated styrene glycol (SG) in blood, and conjugated SG, mandelic acid (MA) and phenylglyoxylic acid (PGA) in urine. Results: Average pulmonary retention of styrene was 62%. Excretion of the acidic metabolites MA and PGA accounted for 58% of the pulmonary uptake. The average maximum concentration (C max ) and area under the curve (AUC) of free (R)-SG in blood were 1.3 and 1.7 times higher than those of (S)-SG respectively; the half-life of (R)-SG was longer (82 vs 62 min, P < 0.005). C max and AUC of the conjugated SG enantiomers in blood did not di er, but again half-life for (R)-SG was longer (72 vs 64 min, P < 0.05). Cumulative excretion and renal clearance of conjugated (S)-SG in urine were three and four times higher, respectively, than that of (R)-SG. Cumulative excretion of (S)-MA was 1.6 times higher than (R)-MA. Interindividual di erences in the kinetic parameters of the metabolites were two-to threefold. Conclusions: The enantiomeric excess found was di erent for each metabolite under study, implying di erent enantioselectivity and/or enantiospeci®city of the enzymes and carrier-proteins involved in the biotransformation and excretion. The use of these metabolites as biological indicators for prediction of the enantiomeric excess of the toxic metabolite styrene-7,8-oxide (SO) is therefore not justi®ed. Interindividual di erences in the stereochemical metabolism of styrene are moderate.

Development of Enantioselective Polyclonal Antibodies to Detect Styrene Oxide Protein Adducts

“…Recently, we prepared a polyclonal antibody as an experimental tool to detect racemic SO modified proteins . The effort in the development of antibodies to selectively detect protein adducts modified by SO enantiomers was inspired by the findings of toxic effects of SO with enantiomeric differentiation. − The availability of the antibodies would assist us to investigate the enantiomeric role of SO in styrene-mediated toxicity. A number of immunoassays developed for analysis of chiral drugs, such as propanolol, alprenolol, and pentobarbital, ractopamine, finrozole, and S-20499, have been reported.…”

“…Styrene oxide has one chiral center with two optical isomers as shown in Scheme . It was reported that the ( R )-styrene oxide ( R SO) was preferentially formed in mice, especially in the lung, whereas the ( S )-styrene oxide ( S SO) was preferentially generated in rats. − In human volunteers, the cumulative excretion of the ( S ) - enantiomer of styrene glycol and mendelic acid were higher than the R form after exposure to styrene . In human liver microsomes, cytochrome P450-mediated styrene oxidation showed the production of more S SO relative to R SO .…”

“…22-24 In human volunteers, the cumulative excretion of the ( S )-enantiomer of styrene glycol and mendelic acid were higher than the R form after exposure to styrene. 25 In human liver microsomes, cytochrome P450-mediated styrene oxidation showed the production of more S SO relative to R SO. 26 It was also found that S SO was preferentially hydrolyzed than R SO in human liver microsomes.…”

Liquid chromatography/electrospray tandem mass spectrometry characterization of styrene metabolism in man and in rat

“…Styrene‐derived glucuronide and sulfate conjugates can also be formed from other intermediate hydroxylated metabolites, such as styrene glycol (SG) and 1‐ and 2‐phenylethanol (PE). The urinary excretion of SG conjugates, as well as free and conjugated SG in blood, has recently been investigated in 20 healthy volunteers exposed to 360 mg/m 3 (84.7 ppm) sty‐rene for 1 h during physical exercise with the aim of studying the inter‐individual variability in the stereochemistry of styrene metabolism 18. SG excretion, determined after hydrolysis of urine and blood samples, accounted for about 1% of that of MA, where free SG in urine is less than 5% of the total SG content.…”