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Human metabolism of Δ3-carene and renal elimination of Δ3-caren-10-carboxylic acid (chaminic acid) after oral administration

  • Toxicokinetics and Metabolism
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Abstract

We studied the human in vivo metabolism of Δ3-carene (CRN), a natural monoterpene which commonly occurs in the human environment. Four healthy human volunteers were orally exposed to a single dose of 10 mg CRN. Each volunteer gave one urine sample before administration and subsequently collected each urine sample within 24 h after administration. The concentration of the proposed CRN metabolites Δ3-caren-10-ol (CRN-10-OH), Δ3-caren-10-carboxylic acid (chaminic acid, CRN-10-COOH), and Δ3-caren-3,4-diol (CRN-3,4-OH) were determined using a very specific and sensitive GC–MS/MS procedure. Other CRN metabolites were investigated using GC–PCI–MS Q1 scan analyses. CRN-10-COOH was detected in each urine sample with maximum concentration (113.0–1,172.9 µg L−1) 2–3 h after administration, whereas CRN-10-OH and CRN-3,4-OH were not detected in any of the samples. The renal excretion kinetics of CRN-10-COOH showed an elimination half-life of about 3 h. The cumulative excretion of CRN-10-COOH within 24 h after exposure correlated with about 2 % of the applied dose. The GC–PCI–MS Q1 scan analysis indicated several additional human CRN metabolites; thereof, six spectra enabled the prediction of the corresponding chemical structure. The results of the study indicate that CRN-10-COOH is a relevant product of the human in vivo metabolism of CRN. The oxidation of its allylic methyl group proceeds until the acidic structure without interruption. Thus, the generation of the alcoholic intermediate appeared to be the rate-determining step of this metabolic route. Nevertheless, the proportion of CRN-10-COOH in the CRN metabolism is low, and other oxidative metabolites are likely. This hypothesis was confirmed by the discovery of additional human CRN metabolites, whose predicted chemical structures fit in with further oxidative products of CRN metabolism.

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Acknowledgments

The authors are grateful to the volunteers for taking part in the oral exposure study and to Mr. Jürgen Bienert (MPI bpc) for recording NMR and mass spectra. This study was supported by a grant from the Adolf Rohrschneider-Stiftung (Erlangen, Germany).

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Authors and Affiliations

  1. Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, University of Erlangen-Nuremberg, Schillerstrasse 25/29, 91054, Erlangen, Germany

    Lukas Schmidt & Thomas Göen

  2. Facility for Synthetic Chemistry, Max Planck Institute for Biophysical Chemistry (MPI bpc), Am Fassberg 11, 37077, Göttingen, Germany

    Vladimir N. Belov

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  1. Lukas Schmidt
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  2. Vladimir N. Belov
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  3. Thomas Göen
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Correspondence to Thomas Göen.

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Schmidt, L., Belov, V.N. & Göen, T. Human metabolism of Δ3-carene and renal elimination of Δ3-caren-10-carboxylic acid (chaminic acid) after oral administration. Arch Toxicol 89, 381–392 (2015). https://doi.org/10.1007/s00204-014-1251-5

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  • DOI: https://doi.org/10.1007/s00204-014-1251-5

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