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Research ArticleArticle

COMPARATIVE METABOLISM OF GERANYL NITRILE AND CITRONELLYL NITRILE IN MOUSE, RAT, AND HUMAN HEPATOCYTES

Raymond A. Kemper, Diane L. Nabb, Shawn A. Gannon, Timothy A. Snow and Anne Marie Api
Drug Metabolism and Disposition June 2006, 34 (6) 1019-1029; DOI: https://doi.org/10.1124/dmd.105.005496
Raymond A. Kemper
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Diane L. Nabb
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Shawn A. Gannon
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Timothy A. Snow
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Anne Marie Api
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Abstract

Geranyl nitrile (GN) and citronellyl nitrile (CN) are fragrance components used in consumer and personal care products. Differences in the clastogenicity of these two terpenes are postulated to result from differential biotransformation, presumably involving the conjugated nitrile moiety. The metabolic clearance and biotransformation of GN and CN were compared in primary hepatocytes from mice, rats, and humans. For determination of intrinsic clearance, GN and CN were incubated with hepatocytes in sealed vials, and the headspace was sampled periodically by solid-phase microextraction and analyzed by gas chromatography/mass spectrometry. For metabolite identification, GN and CN were incubated with hepatocytes from each species for 60 min, and reaction mixtures were extracted and analyzed by mass spectroscopy. Both GN and CN were rapidly metabolized in hepatocytes from all species (T1/2, 0.7-11.6 min). Within a species, intrinsic clearance was similar for both compounds and increased in the order human < rat << mouse. Major common pathways for biotransformation of GN and CN involved 1) epoxidation of the 6-alkenyl moiety followed by conjugation with glutathione, 2) hydroxylation of the terminal methyl group(s) followed by direct conjugation with glucuronic acid in rodents or further oxidation to the corresponding acid in human cells, and 3) hydroxylation of the allylic C5 position. No evidence for either phase I or phase II metabolism of the conjugated nitrile moiety was obtained. Thus, the presumed metabolic basis for differences in genotoxicity remains elusive.

Footnotes

  • This research was supported by the Research Institute for Fragrance Materials (RIFM), Woodcliff Lake, NJ.

  • This work was presented in part at the 44th annual meeting of the Society of Toxicology, March 6-10, 2005; New Orleans, LA.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.105.005496.

  • ABBREVIATIONS: GN, geranyl nitrile; CN, citronellyl nitrile; GC/MS, gas chromatography/mass spectrometry; SPME, solid-phase microextraction; HPLC, high-performance liquid chromatography; EI, electron impact; m-CPBA, m-chloroperoxybenzoic acid; LC/MS, liquid chromatography/mass spectrometry; GNO, 6,7-epoxygeranyl nitrile; 8-hydroxy-CN, 8-hydroxy-3,7-dimethyloct-6-ene nitrile.

    • Received May 13, 2005.
    • Accepted March 14, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (6)
Drug Metabolism and Disposition
Vol. 34, Issue 6
1 Jun 2006
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Research ArticleArticle

COMPARATIVE METABOLISM OF GERANYL NITRILE AND CITRONELLYL NITRILE IN MOUSE, RAT, AND HUMAN HEPATOCYTES

Raymond A. Kemper, Diane L. Nabb, Shawn A. Gannon, Timothy A. Snow and Anne Marie Api
Drug Metabolism and Disposition June 1, 2006, 34 (6) 1019-1029; DOI: https://doi.org/10.1124/dmd.105.005496

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Research ArticleArticle

COMPARATIVE METABOLISM OF GERANYL NITRILE AND CITRONELLYL NITRILE IN MOUSE, RAT, AND HUMAN HEPATOCYTES

Raymond A. Kemper, Diane L. Nabb, Shawn A. Gannon, Timothy A. Snow and Anne Marie Api
Drug Metabolism and Disposition June 1, 2006, 34 (6) 1019-1029; DOI: https://doi.org/10.1124/dmd.105.005496
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