Ptaquiloside, carcinogen

CC 1065 108 is a highly toxic antibiotic isolated from Streptomyces zelensis containing a reactive spirocyclopropane ring. It cleaves DNA through a mechanism similar to the cleavage which occurs upon treatment of DNA with the carcinogenic ptaquiloside 25 (vide supra. Sect. 2.6), namely by depurination of alkyladenine adducts, Eq. (43) [142]. 

A review on the isolation, chemistry, and biochemistry of the bracken fern (Pte-ridium aquilinum) carcinogen ptaquiloside (P) has been published (527). This fem and others contain the pterosins that were summarized previously (7). No new examples were reported in the interim. 

Kigoshi, H., Sawada, A., Niwa, H., andYamada, K., Synthesis of a functionalized carbocychc skeleton of ptaquUosin, the aglycone of a bracken carcinogen ptaquiloside based on an intramolecular Diels-Alder reaction. Bull. Chem. Soc. Jpn., 62, 1639, 1989. 

A toxic component of braken fern, perhaps either quercetin (105) or ptaquiloside, a glucoside (106), has a mixed history of carcinogenicity. It is sometimes impHcated in an increased incidence of bladder cancer in animals and esophageal cancer in humans. Multiple other dietary components seem to either promote or interfere with its action, and the significance of braken fern in human carcinogenesis remains unproven. 

By using the hepatocyte primary culture DNA repair test [247] with liver cells of adult ACI rats, an essay that is capable to discern true carcinogens from solely mutagenic compounds such as quercetin and other bioactive flavonoids, Japanese workers [248] were able to show that ptaquiloside is a genotoxic carcinogen. The key evidence was that ptaquiloside induced DNA repair in the exposed liver cells, which could be interpreted as an intrusion into the DNA molecule that caused enough distortions to trigger the reconstruction mechanism. 

While this theory was shaping up to account for ptaquiloside carcinogenicity, some inconsistencies appeared. Extensive examination of several alkylating agents revealed the existence of a correlation between the site of alkylation in DNA and the final effect [257]. Alkylation at the 06 of guanine, O2 and O4 of thymine, and O2 of cytosine in the DNA polymer could be correlated with procarcinogenicitv, whereas reactions at the nitrogen positions of the heterocycles resulted in enhanced levels of cytotoxicity. Application of the hard-soft acid-base HSAB theory [258,259] to alkylation of DNA nucleosides [260] provided support to this view. APT (14) may be classified as a semi-hard electrophile which is be prone to react with less hard N over harder O nucleophiles. If so,... 

A number of sesquiterpenes have pronounced biological activity both in the plants themselves and toward other organisms. Illudane sesquiterpenes such as ptaquiloside (24) from bracken and several other ferns are responsible for the carcinogenic activity of these plants, including some used as food products (Fig. 21.10) (Saito et al., 1990). 

Ptaquiloside is an instable glucoside present in the widely distributed bracken fern (Pteridium aquilinum). Under alkaline conditions, it is converted in a conjugated diene-one which is readily added to various nucleophilic compounds. Therefore, it has a carcinogenic potency [9]. 

Hirono, I., S. Aiso, T. Yamaji, H. Mori, K. Yamada, H. Niwa, M. Ojika, K. Wakamatsu, H. Kigoshi, K. Niiyama, and Y. Uosaki Carcinogenicity in Rats of Ptaquiloside Isolated from Bracken. Gann 75, 833 (1984). 

Matoba, M., E. Saito, K. Saito, K. Koyama, S. Natori, T. Matsushima, and M. Takimoto Assay of Ptaquiloside, the Carcinogenic Principle of Bracken, Pteridium aquilinum by Mutagenicity Testing in Salmonella typhimurium TA98. Mutagenesis. In press. 

---