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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 393, Issue 2, pp 213–223 | Cite as

Metabolism of carcinogenic alpha-asarone by human cytochrome P450 enzymes

  • Alexander T. CartusEmail author
  • Dieter Schrenk
Original Article
  • 108 Downloads

Abstract

Major metabolites of alpha-asarone in liver microsomes are epoxide-derived side-chain diols. The intermediately formed epoxides are mutagenic and form DNA adducts and thus are likely responsible for the (hepato) carcinogenic effect of alpha-asarone observed in male mice. We here investigated the role of eight human cytochrome P450 enzymes (CYP1A1, 1A2, 2A6, 2B6, 2C19, 2D6, 2E1, and 3A4) in the metabolism of alpha-asarone using Supersomes™. The epoxidation of the side-chain of alpha-asarone was mainly catalyzed by CYP3A4 and to a lesser extent by 2B6 and 1A1 whereas the hydroxylation of the side-chain leading to (E)-3′-hydroxyasarone was catalyzed by all investigated CYPs excluding CYP2A6. O-demethylation was catalyzed by CYP1A1, 2A6, 2B6, and 2C19. Applying relative activity factors (RAF) to the observed formation rates revealed that CYP3A4, at least at lower substrate concentrations, is nearly solely responsible for the formation of the mutagenic side-chain epoxides of alpha-asarone. Comparison of the RAF-corrected formation rates of all metabolites with those found in incubation with human liver microsomes revealed that the side-chain hydroxylation and epoxidation can be explained in good approximation by the tested hepatic CYPs, whereas other CYPs or enzymes may contribute to the O-demethylation of alpha-asarone. Therefore, the capacity for metabolic activation of alpha-asarone has to be expected to be widely present among the general population.

Keywords

Asarone Cytochrome P450 Metabolism Carcinogenicity Alkenylbenzene 

Notes

Author contribution

AC conceived and designed the research, conducted the experiments, analyzed the data, and wrote the manuscript. DS participated in drafting the manuscript and revised it critically. Both authors read and approved the manuscript.

Funding information

This work was funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG) under grant #SCHR 327/14-1.

Compliance with ethical standards

Conflict of interest

The authors declare that there are no conflicts of interest.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Technische Universität Kaiserslautern, Food Chemistry and ToxicologyKaiserslauternGermany

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