Bracken Fern Carcinogen, Ptaquiloside, Forms a Guanine O⁶-Adduct in DNA

Bracken fern (Pteridium sp.) is a viable and vigorous plant with invasive potential, ingestion of which causes chronic illness and cancers in farm animals. Bracken is a suspected human carcinogen, and exposure can result from ingestion of bracken-contaminated water, dairy products, or meat derived from livestock grazing on bracken fern. Bracken is also consumed in the diets of some communities. Ptaquiloside (PTQ), a known bracken carcinogen, is an illudane-type glycoside that forms a highly reactive electrophile, PTQ dienone, known to produce N⁷-guanine and N³-adenine adducts in DNA. Here, we demonstrate for the first time that PTQ dienone also produces an O⁶-alkylguanine (O⁶-PTBguanine) in DNA. Since O⁶-alkylguanines in DNA can be mutagenic, this work provides a potential mechanistic link between PTQ exposure and carcinogenicity. O⁶-PTBguanine is poorly repaired by O⁶-methylguanine-DNA methyltransferase that acts on other O⁶-alkylguanines, further highlighting the potential risk of exposure to bracken and PTQ.