Formation of DNA-Protein Cross-Links in Mammalian Cells by Levuglandin E2

Abstract

Levuglandin E2(LGE2), a rearrangement product derived from the prostaglandin endoperoxide, PGH2, causes repair-resistant DNA–protein cross-links and cell death (LD50 = 230 nM) in V79 Chinese hamster lung fibroblasts. The half-life for sequestration of LGE2 by covalent binding to cellular nucleophiles is at least an hour for 10 μM LG. This suggests that the in vivo production and distribution of free LGs should be measurable on this time scale. Following removal of the LGE2 and the return of the cultures to normal growth medium, additional DNA–protein cross-links continued to form over the ensuing 6–24 h. The results suggest that LG adducts to DNA or protein are not repaired, but react further at sites on protein or DNA in close proximity to the initial adducts, forming cross-links in a slow phase of the process. © 1993, American Chemical Society. All rights reserved.