Dietary Antioxidants:Prevention of Deletion Mutations

#C172 Can Dietary Antioxidants Prevent Deletion Mutations?

Catherine B. Klein,1 Kanae Mure,2 Joanna Leszczynska,1 Joshua Matz,1 Audrey King,1 Toby G. Rossman.1

NYU School of Medicine,1 Tuxedo, NY, Wakayama Medical University,2 Wakayama City, Wakayama, Japan.

Chemoprevention can occur on many levels, including at the earliest stages of cancer cell initiation. At that level, numerous dietary antioxidants have been shown to moderate or prevent mutations and other genotoxic endpoints in a variety of experimental systems in vitro and in vivo.

Using two different in vitro mammalian cell culture models, we have investigated the antimutagenic potential of several dietary antioxidants, including the vitamin supplements a-tocopherol and ascorbate, the tomato-derived carotenoid lycopene, and the green tea polyphenol (-)-epigallocatechin gallate (EGCG).

In human mismatch repair deficient (hMLH1-) HCT116 cells derived from a patient with hereditary nonpolyposis colorectal cancer (HNPCC, Lynch Syndrome II), all four antioxidants are quite efficient at reducing the inherent high levels of spontaneous mutagenesis characteristic of these cells.

Lycopene was the most effective antimutagen in this group, reducing the spontaneous mutation rate at the hprt locus by about 70% over several weeks of continuous culture of the cells.

In studies aimed at investigating the mechanism by which lycopene reduced the accumulation of spontaneous mutations in these cells, analysis of the spectrum of recoverable hprt mutations shows a significant shift in favor of deletions among the mutants isolated from the lycopene-treated cultures.

Thus, while lycopene greatly reduced the mutant yield in exposed cell cultures, it primarily eliminated spontaneous base substitution mutations leaving the deletion mutations to predominate in these cultures.

In support of this finding, data obtained using the gpt transgenic Chinese hamster G12 cells shows that X-ray induced deletion mutants are also selectively retained (not inhibited) in cultures pre-treated with catalase or vitamin E. Similar studies in G12 cells with X-rays and lycopene are currently ongoing.

Whereas antioxidants appear to inhibit both spontaneous and carcinogen-induced mutations, most likely by scavenging mutagenic reactive oxygen radicals, in these studies they are less effective against preventing deletion mutations which can ultimately lead to loss of heterozygosity of cancer suppressing genes.

In addition to beginning to understand the mechanisms by which dietary antioxidants may prevent mutagenic damage in mammalian cells, these findings also challenge the concept that deletion mutations comprise a significant portion of the DNA oxidation spectra.

In summary, our studies on the analysis of mutation spectra in antioxidant-exposed mammalian cells suggests that antioxidants do not effectively prevent deletion mutations of spontaneous or carcinogen induced origin.

Supported by CA89732, CA73610, ES09845, and T32 ES07324

Frontiers in Cancer Prevention Research, 2003 AACR

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