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Rapid CommunicationShort Communication

Species Differences in Microsomal Oxidation and Glucuronidation of 4-Ipomeanol: Relationship to Target Organ Toxicity

Oliver T. Parkinson, Aaron M. Teitelbaum, Dale Whittington, Edward J. Kelly and Allan E. Rettie
Drug Metabolism and Disposition October 2016, 44 (10) 1598-1602; DOI: https://doi.org/10.1124/dmd.116.070003
Oliver T. Parkinson
Departments of Medicinal Chemistry (O.T.P., A.M.T., D.W., A.E.R.) and Pharmaceutics (E.J.K.), University of Washington, Seattle, Washington
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Aaron M. Teitelbaum
Departments of Medicinal Chemistry (O.T.P., A.M.T., D.W., A.E.R.) and Pharmaceutics (E.J.K.), University of Washington, Seattle, Washington
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Dale Whittington
Departments of Medicinal Chemistry (O.T.P., A.M.T., D.W., A.E.R.) and Pharmaceutics (E.J.K.), University of Washington, Seattle, Washington
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Edward J. Kelly
Departments of Medicinal Chemistry (O.T.P., A.M.T., D.W., A.E.R.) and Pharmaceutics (E.J.K.), University of Washington, Seattle, Washington
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Allan E. Rettie
Departments of Medicinal Chemistry (O.T.P., A.M.T., D.W., A.E.R.) and Pharmaceutics (E.J.K.), University of Washington, Seattle, Washington
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Abstract

4-Ipomeanol (IPO) is a model pulmonary toxicant that undergoes P450-mediated metabolism to reactive electrophilic intermediates that bind to tissue macromolecules and can be trapped in vitro as the NAC/NAL adduct. Pronounced species and tissue differences in IPO toxicity are well documented, as is the enzymological component of phase I bioactivation. However, IPO also undergoes phase II glucuronidation, which may compete with bioactivation in target tissues. To better understand the organ toxicity of IPO, we synthesized IPO-glucuronide and developed a new quantitative mass spectrometry–based assay for IPO glucuronidation. Microsomal rates of glucuronidation and P450-dependent NAC/NAL adduct formation were compared in lung, kidney, and liver microsomes from seven species with different target organ toxicities to IPO. Bioactivation rates were highest in pulmonary and renal microsomes from all animal species (except dog) known to be highly susceptible to the extrahepatic toxicities induced by IPO. In a complementary fashion, pulmonary and renal IPO glucuronidation rates were uniformly low in all experimental animals and primates, but hepatic glucuronidation rates were high, as expected. Therefore, with the exception of the dog, the balance between microsomal NAC/NAL adduct and glucuronide formation correlate well with the risk for IPO-induced pulmonary, renal, and hepatic toxicities across species.

Footnotes

    • Received February 11, 2016.
    • Accepted July 22, 2016.
  • This study was supported in part by the National Institutes of Health [grant R01GM49054] and by the University of Washington School of Pharmacy Brady Fund for Natural Products.

  • dx.doi.org/10.1124/dmd.116.070003.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (10)
Drug Metabolism and Disposition
Vol. 44, Issue 10
1 Oct 2016
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Rapid CommunicationShort Communication

Species Differences in 4-Ipomeanol Microsomal Metabolism

Oliver T. Parkinson, Aaron M. Teitelbaum, Dale Whittington, Edward J. Kelly and Allan E. Rettie
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1598-1602; DOI: https://doi.org/10.1124/dmd.116.070003

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Rapid CommunicationShort Communication

Species Differences in 4-Ipomeanol Microsomal Metabolism

Oliver T. Parkinson, Aaron M. Teitelbaum, Dale Whittington, Edward J. Kelly and Allan E. Rettie
Drug Metabolism and Disposition October 1, 2016, 44 (10) 1598-1602; DOI: https://doi.org/10.1124/dmd.116.070003
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