GENOTOXIC PYRROLIZIDINE ALKALOIDS AND PYRROLIZIDINE ALKALOID<i>N</i>-OXIDES—MECHANISMS LEADING TO DNA ADDUCT FORMATION AND TUMORIGENICITY

Abstract

Plants that contain pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides are widely distributed in the world. These plants are probably the most common poisonous plants affecting livestock, wildlife, and humans. Although pyrrolizidine alkaloids have been shown to be genotoxic, including tumorigenic in experimental animals, the mechanisms of tumor formation have not been fully understood. Our recent studies on riddelliine, riddelline N-oxide, and dehydroretronecine (DHR) provided evidence suggesting that pyrrolizidine alkaloids and pyrrolizidine alkaloid N-oxides induce tumors via a genotoxic mechanism, and that tumorigenicity is mediated by a set of eight DHR-derived DNA adducts. This mechanism may be general to other carcinogenic pyrrolizidine alkaloids and may also be responsible for the other genotoxicities of pyrrolizidine alkaloids, including mutagenicity and teratogenicity. It is hypothesized that these DHR-derived DNA adducts are potential biomarkers of pyrrolizidine alkaloid tumorigenicity.