Scientific Publications by FDA Staff

J Environ Sci Health C 2016 Jan 2;34(1):57-76

7-cysteinyl-pyrrole conjugate--a new potential DNA reactive metabolite of pyrrolizidine alkaloids.

He X, Xia Q, Ma L, Fu PP

Pyrrolizidine alkaloids (PAs) require metabolic activation to exert cytotoxicity, genotoxicity, and tumorigenicity. We previously reported that (+/-)-6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived DNA adducts are responsible for PA-induced liver tumor formation in rats. In this study, we determined that metabolism of riddelliine and monocrotaline by human or rat liver microsomes produced 7-cysteine-DHP and DHP. The metabolism of 7-glutathionyl-DHP by human and rat liver microsomes also generated 7-cysteine-DHP. Furthermore, reaction of 7-cysteine-DHP with calf thymus DNA in aqueous solution yielded the above-described DHP-derived DNA adducts. This study represents the first report that 7-cysteine-DHP is a new PA metabolite that can lead to DNA adduct formation.