Humans and animals can be exposed to carcinogenic
pyrrolizidine alkaloids (PAs) through consumption of plants commonly found in many parts of the world. Although the liver is the primary target organ for carcinogenic PAs, they have also induced lung
tumors in rodents. Hepatic
cytochrome P450 activity converts PAs into dehydro-PAs that can be hydrolyzed to dehydropyrrolizidine (DHP); these reactive pyrrolic metabolites can produce four characteristic
DNA adducts associated with PA-induced liver
tumor initiation in laboratory animals. We reported recently that these four
DNA adducts are also formed when
7-glutathione-DHP (7-GS-DHP) or
7-cysteine-DHP is incubated with
calf thymus DNA. Here we showed that the four characteristic
DNA adducts were formed when human A549 brochoalveolar
carcinoma cells were treated with three dehydro-PAs (dehydroriddelliine,
dehydromonocrotaline, or
dehydroretronecine) or with 7-GS-DHP or
7-cysteine-DHP. For comparison, two parent PAs (
riddelliine and
monocrotaline) and 7,9-di-glutathionine-DHP were studied. No DHP-
DNA adducts were detected with these incubations, confirming that A549 lung
carcinoma cells do not express
cytochrome P450 enzymes required for metabolic activation of PAs. Our results show that primary and secondary pyrrolic metabolites of carcinogenic PAs produce characteristic DHP-containing
DNA adducts in A549
lung cancer cells, suggesting that they are
DNA reactive metabolites.