Abstract
Micromolar concentrations of fecapentaene-12, a mutagen found in human feces, decrease survival measured as colony-forming efficiency and membrane integrity of cultured human fibroblasts. Fecapentaene-12 also decreases the content of cellular free low-molecular-weight thiols including glutathione. Fecapentaene-12 reacts directly with glutathione by causing both decreased levels of free thiol and some concomitant formation of oxidized glutathione, indicating that thiol depletion is a result of both alkylation and oxidative reactions. Exposure of cells to 2 or 5 µm fecapentaene-12 causes significant amounts of DNA-interstrand cross-links and DNA-single strand breaks, respectively, whereas exposure to a higher concentration of fecapentaene-12, i.e., 10 µm, also causes significant DNA-protein cross-links. Results from the reaction of fecapentaene-12 with isolated plasmid DNA parallel the cellular pattern of DNA damage; primarily interstrand cross-links and strand breaks occur also in plasmid DNA. Taken together, these studies show that fecapentaene-12 is a potent cytotoxic and genotoxic agent which can react with cellular thiols and cause several types of DNA damage.
Footnotes
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↵1 J. M. D., C. C. E., K. S., and R. C. G. were supported in part by grants from the Swedish National Board of Laboratory Animals, the Swedish Medical Research Council, the Swedish Cancer Society, the Swedish Natural Science Resource Council, the Swedish Fund for Scientific Research without Animal Experiments, and Lions Club International, Djurgården, Stockholm, Sweden.
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↵2 To whom requests for reprints should be addressed, at Department of Toxicology, Karolinska Institutet, Box 60400, S-104 01 Stockholm, Sweden.
- Received December 12, 1988.
- Revision received June 19, 1989.
- Accepted July 12, 1989.
- ©1989 American Association for Cancer Research.
Volume 49, Issue 21
