1-Formyl-7-hydroxy-6,7-dihydro-5H-pyrrolizine (1-CHO-DHP)-Cysteine Conjugates: Metabolic Formation and Binding to Cellular DNA.

Abstract

1-Formyl-7-hydroxy-6,7-dihydro-5H-pyrrolizine (1-CHO-DHP) is a potential proximate carcinogenic metabolite of pyrrolizidine alkaloids. In the present study, we determined that the reaction of 1-CHO-DHP with cysteine generated four identified products. By mass and 1H NMR spectral analyses, these products are cysteinyl-[2'-S-7]-1-CHO-DHP (P2), cysteinyl-[3'-N-7]-1-CHO-DHP (P3), 7-keto-DHP (P4), and 1-cysteinylimino-DHP (P5). These four compounds were also formed from the incubation of 1-CHO-DHP in HepG2 cells. Compounds P3 and P5 were interconvertible in acetonitrile and water. Incubation of P2 in HepG2 cells generated the four DHP-dG and -dA adducts that we propose to be potential common biomarkers of pyrrolizidine alkaloids exposure and pyrrolizidine alkaloids-induced liver tumor initiation. These four DHP-DNA adducts were also formed from the incubation of a mixture of P3 and P5 in HepG2 cells but not from the incubation with 7-keto-DHP. From the reaction of 1-CHO-DHP with glutathione, only trace amounts of the glutathione-1-CHO-DHP adduct were detected, with the structure unable to be characterized.

• Authors: Xiaobo He, Qingsu Xia, Yuewei Zhao, Peter P Fu
• Journal: Chemical research in toxicology (Chem Res Toxicol) Vol. 33 Issue 8 Pg. 2139-2146 (08 17 2020) ISSN: 1520-5010 [Electronic] United States
• PMID: 32588618 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• 1-CHO-DHP
• Pyrrolizidine Alkaloids
• DNA
• Cysteine

Topics

• Animals
• Binding Sites
• Cysteine (chemistry, metabolism)
• DNA (chemistry, metabolism)
• Hep G2 Cells
• Hepatocytes (chemistry, metabolism)
• Humans
• Male
• Molecular Structure
• Pyrrolizidine Alkaloids (chemistry, metabolism)
• Rats