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Sulfotransferase-independent genotoxicity of illudin S and its acylfulvene derivatives in bacterial and mammalian cells

  • Genotoxicity and Carcinogenicity
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Abstract

Acylfulvenes are a class of antitumor agents derived from illudin S, a sesquiterpenoid toxin isolated from mushrooms of the genus Omphalotus. Although DNA appears to be their major target, no data concerning mutagenicity of acylfulvenes are available in the literature, and limited data have been published on illudin S. Enzyme-mediated biotransformations have been demonstrated to influence the cytotoxicity of acylfulvenes. Illudin S and some acylfulvenes [e.g., (−)-6-hydroxymethylacylfulvene (HMAF)] are allylic alcohols with potential for enhanced cytotoxicity and genotoxicity by means of metabolic sulfation. Therefore, we studied the influence of various heterologously expressed human sulfotransferases (SULTs) on biological activities of illudin S and HMAF in bacterial and mammalian cells. (−)-Acylfulvene (AF) was tested as a congener lacking an allylic hydroxyl group. We found: (1) all three compounds were mutagenic in standard Salmonella typhimurium strains TA98, TA100 and TA104; (2) they induced gene mutations (at the hypoxanthine phosphoribosyl transferase locus) and sister chromatid exchange (SCE) in Chinese hamster V79 cells; (3) these effects were practically unaffected when human SULTs were expressed in the target bacteria or mammalian cells (using SCE as the endpoint); (4) illudin S demonstrated 40–600 times higher genotoxic activities than the semisynthetic acylfulvenes studied; it was positive in the SCE test even at a concentration of 0.3 nM; (5) genotoxicity in mammalian cells was observed at substantially lower concentrations of the compounds than required for a positive result in the bacterial test (400 nM with illudin S). We conclude that illudin S, HMAF and AF are potent genotoxicants and human SULTs do not play a significant role in their bioactivation.

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Abbreviations

AF:

(−)-Acylfulvene

HMAF:

(−)-6-Hydroxymethylacylfulvene

hprt :

Hypoxanthine phosphoribosyl transferase gene

PTGR1:

NADPH-dependent prostaglandin reductase 1

SCE:

Sister chromatid exchange

SULT:

Sulfotransferase

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Acknowledgments

We thank Ms. Andrea Katschak and Jutta Schwenk for excellent technical assistance.

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Authors and Affiliations

  1. Department of Nutritional Toxicology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke, Arthur-Scheunert-Allee 114-116, 14558, Nuthetal, Germany

    Hansruedi Glatt & Walter Meinl

  2. Department of Health Sciences and Technology, Institute of Food, Nutrition and Health, ETH Zurich, Schmelzbergstrasse 9, Zurich, 8092, Switzerland

    Kathryn E. Pietsch & Shana J. Sturla

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  1. Hansruedi Glatt
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  2. Kathryn E. Pietsch
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  3. Shana J. Sturla
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  4. Walter Meinl
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Correspondence to Hansruedi Glatt.

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Glatt, H., Pietsch, K.E., Sturla, S.J. et al. Sulfotransferase-independent genotoxicity of illudin S and its acylfulvene derivatives in bacterial and mammalian cells. Arch Toxicol 88, 161–169 (2014). https://doi.org/10.1007/s00204-013-1097-2

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  • DOI: https://doi.org/10.1007/s00204-013-1097-2

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