The 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, from dairy products or meat derived from livestock grazing on bracken fern. Bracken is also consumed in the diet 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 (MGMT) that acts on other O6-alkylguanines, further highlighting the potential risk of exposure to bracken and PTQ.