Absolute configuration, stability, and interconversion of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine valine adducts and their phenylthiohydantoin derivatives

Xiao Jiang; Shuguang Wang; Yuewei Zhao; Qingsu Xia; Lining Cai; Xin Sun; Peter P Fu

doi:10.1016/j.jfda.2015.01.004

Absolute configuration, stability, and interconversion of 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine valine adducts and their phenylthiohydantoin derivatives

J Food Drug Anal. 2015 Jun;23(2):318-326. doi: 10.1016/j.jfda.2015.01.004. Epub 2015 Feb 18.

Authors

Xiao Jiang¹, Shuguang Wang², Yuewei Zhao², Qingsu Xia², Lining Cai³, Xin Sun⁴, Peter P Fu⁵

Affiliations

¹ Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA; National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China.
² Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA.
³ Biotranex LLC, Monmouth Junction, NJ, USA.
⁴ National Institute of Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China.
⁵ Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, AR, USA. Electronic address: peter.fu@fda.hhs.gov.

Abstract

Pyrrolizidine alkaloid-containing plants are widespread in the world and probably the most common poisonous plants affecting livestock, wildlife, and humans. Pyrrolizidine alkaloids require metabolic activation to form dehydropyrrolizidine alkaloids that bind to cellular proteins and DNA leading to hepatotoxicity, genotoxicity, and tumorigenicity. At present, it is not clear how dehydropyrrolizidine alkaloids bind to cellular amino acids and proteins to induced toxicity. We previously reported that reaction of dehydromonocrotaline with valine generated four highly unstable 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP)-derived valine (DHP-valine) adducts that upon reaction with phenyl isothiocyanate (PITC) formed four DHP-valine-PITC adduct isomers. In this study, we report the absolute configuration and stability of DHP-valine and DHP-valine-PITC adducts, and the mechanism of interconversion between DHP-valine-PITC adducts.

Keywords: 6,7-dihydro-7-hydroxy-1-hydroxymethyl-5H-pyrrolizine (DHP); DHP-valine adducts; DHP-valine-phenyl isothiocyanate adducts; interconversion; liquid chromatography–electrospray tandem mass spectrometry; phenylthiohydantoin adducts; pyrrolizidine alkaloid.