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Research ArticleArticle

In Vitro Metabolism of Isoline, a Pyrrolizidine Alkaloid from Ligularia duciformis, by Rodent Liver Microsomal Esterase and Enhanced Hepatotoxicity by Esterase Inhibitors

Jun Tang, Teruaki Akao, Norio Nakamura, Zheng-Tao Wang, Kiyoshi Takagawa, Masakiyo Sasahara and Masao Hattori
Drug Metabolism and Disposition October 2007, 35 (10) 1832-1839; DOI: https://doi.org/10.1124/dmd.107.016311
Jun Tang
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Teruaki Akao
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Norio Nakamura
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Zheng-Tao Wang
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Kiyoshi Takagawa
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Masakiyo Sasahara
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Masao Hattori
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Abstract

Isoline, a major retronecine-type pyrrolizidine alkaloid (PA) from the Chinese medicinal herb Ligularia duciformis, was suggested to be the most toxic known PA. Its in vitro metabolism was thus examined in rat and mouse liver microsomes, and its toxicity was compared with that of clivorine and monocrotaline after i.p. injection in mice. Isoline was more rapidly metabolized by both microsomes than clivorine and monocrotaline and converted to two polar metabolites M1 and M2, which were spectroscopically determined to be bisline (a deacetylated metabolite of isoline) and bisline lactone, respectively. Both metabolites were formed in the presence or absence of an NADPH-generating system with liver microsomes but not cytosol. Their formation was completely inhibited by the esterase inhibitors, triorthocresyl phosphate (TOCP) and phenylmethylsulfonyl fluoride, but not at all or partially by cytochrome P450 (P450) inhibitors, α-naphthoflavone and proadifen (SKF 525A), respectively. These results demonstrated that both metabolites were produced by microsomal esterase(s) but not P450 isozymes. The esterase(s) involved showed not only quite different activities but also responses to different inhibitors in rat and mouse liver microsomes, suggesting that different key isozyme(s) or combinations might be responsible for the deacetylation of isoline. Isoline injected i.p. into mice induced liver-specific toxicity that was much greater than that with either clivorine or monocrotaline, as judged by histopathology as well as serum alanine aminotransferase and aspartate aminotransferase levels. Isoline-induced hepatotoxicity was remarkably enhanced by the esterase inhibitor TOCP but was reduced by the P450 inhibitor SKF 525A, indicating that rodent hepatic esterase(s) played a principal role in the detoxification of isoline via rapid deacetylation in vivo.

Footnotes

  • This research was supported by Grant 39825129 from the Natural Science Foundation of China for outstanding young scientists to Z.W.

  • doi:10.1124/dmd.107.016311.

  • ABBREVIATIONS: PA, pyrrolizidine alkaloid; P450, cytochrome P-450 enzyme; NMR, nuclear magnetic resonance; MS, mass spectrometry; HPLC, high-performance liquid chromatography; TOCP, triorthocresyl phosphate; PMSF, phenylmethylsulfonyl fluoride; ANF, α-naphthoflavone; GSH, glutathione; ALT, alanine aminotransferase; AST, aspartate aminotransferase; PB, phenobarbital sodium; TLC, thin layer chromatography.

    • Received April 18, 2007.
    • Accepted July 13, 2007.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 35 (10)
Drug Metabolism and Disposition
Vol. 35, Issue 10
1 Oct 2007
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Research ArticleArticle

In Vitro Metabolism of Isoline, a Pyrrolizidine Alkaloid from Ligularia duciformis, by Rodent Liver Microsomal Esterase and Enhanced Hepatotoxicity by Esterase Inhibitors

Jun Tang, Teruaki Akao, Norio Nakamura, Zheng-Tao Wang, Kiyoshi Takagawa, Masakiyo Sasahara and Masao Hattori
Drug Metabolism and Disposition October 1, 2007, 35 (10) 1832-1839; DOI: https://doi.org/10.1124/dmd.107.016311

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Research ArticleArticle

In Vitro Metabolism of Isoline, a Pyrrolizidine Alkaloid from Ligularia duciformis, by Rodent Liver Microsomal Esterase and Enhanced Hepatotoxicity by Esterase Inhibitors

Jun Tang, Teruaki Akao, Norio Nakamura, Zheng-Tao Wang, Kiyoshi Takagawa, Masakiyo Sasahara and Masao Hattori
Drug Metabolism and Disposition October 1, 2007, 35 (10) 1832-1839; DOI: https://doi.org/10.1124/dmd.107.016311
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