Identification of nevadensin as an important herb-based constituent inhibiting estragole bioactivation and physiology-based biokinetic modeling of its possible in vivo effect

W.A.A.M. Al-Husainy, A. Paini, A. Punt, J. Louisse, B. Spenkelink, J.J.M. Vervoort, T. Delatour, G. Scholz, B. Schilter, T.B. Adams, P.J. van Bladeren, I. Rietjens

Research output: Contribution to journalArticleAcademicpeer-review

36 Citations (Scopus)

Abstract

Estragole is a natural constituent of several herbs and spices including sweet basil. In rodent bioassays, estragole induces hepatomas, an effect ascribed to estragole bioactivation to 1'-sulfooxyestragole resulting in DNA adduct formation. The present paper identifies nevadensin as a basil constituent able to inhibit DNA adduct formation in rat hepatocytes exposed to the proximate carcinogen 1'-hydroxyestragole and nevadensin. This inhibition occurs at the level of sulfotransferase (SULT)-mediated bioactivation of 1'-hydroxyestragole. The Ki for SULT inhibition by nevadensin was 4 nM in male rat and human liver fractions. Furthermore, nevadensin up to 20 µM did not inhibit 1'-hydroxyestragole detoxification by glucuronidation and oxidation. The inhibition of SULT by nevadensin was incorporated into the recently developed physiologically based biokinetic (PBBK) rat and human models for estragole bioactivation and detoxification. The results predict that co-administration of estragole at a level inducing hepatic tumors in vivo (50 mg/kg bw) with nevadensin at a molar ratio of 0.06, representing the ratio of their occurrence in basil, results in almost 100% inhibition of the ultimate carcinogen 1'-sulfooxyestragole when assuming 100% uptake of nevadensin. Assuming 1% uptake, inhibition would still amount to more than 83%. Altogether these data point at a nevadensin-mediated inhibition of the formation of the ultimate carcinogenic metabolite of estragole, without reducing the capacity to detoxify 1'-hydroxyestragole via glucuronidation or oxidation. These data also point at a potential reduction of the cancer risk when estragole exposure occurs within a food matrix containing SULT inhibitors compared to what is observed upon exposure to pure estragole
Original languageEnglish
Pages (from-to)179-190
JournalToxicology and Applied Pharmacology
Volume245
Issue number2
DOIs
Publication statusPublished - 2010

Keywords

  • naturally-occurring alkenylbenzenes
  • post-labeling analysis
  • x c3h-hej f1-mice
  • dna-adducts
  • human liver
  • intestinal-absorption
  • metabolic-activation
  • potent inhibitors
  • mass-spectrometry
  • safety assessment

Fingerprint Dive into the research topics of 'Identification of nevadensin as an important herb-based constituent inhibiting estragole bioactivation and physiology-based biokinetic modeling of its possible in vivo effect'. Together they form a unique fingerprint.

  • Cite this