An efficient enzymatic system for studying structure-carcinogenicity relationships: metabolism of pyrrolizidine alkaloids by human liver microsomes in the presence of calf thymus DNA, resulting in the formation of DNA adducts.

Abstract

Pyrrolizidine alkaloids (PAs) form a family of toxic and carcinogenic phytochemicals found in plants worldwide. The metabolism of toxic PAs, both in vivo and in vitro, generates four (±)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts, namely, DHP-dG-3, DHP-dG-4, DHP-dA-3, and DHP-dA-4, as documented in previous research. We have proposed that these DHP-DNA adducts play a pivotal role in the induction of liver tumor by PAs in rats and mice, serving as potential common biological biomarkers for PA exposure and carcinogenesis. In this study, we found that the metabolism of PAs and PA N-oxides by human liver microsomes, in the presence of calf thymus DNA, results in the formation of DNA adducts. This process serves as a convenient and biologically significant platform for investigating the structure-carcinogenicity relationships of PAs.