FORMATION OF DNA-PROTEIN CROSS-LINKS IN MAMMALIAN-CELLS BY LEVUGLANDIN-E(2)

Levuglandin E2 (LGE2), a rearrengement product derived from the prosta glandin endoperoxide, PGH2, causes repair-resistant DNA-protein cross- links and cell death (LD50 = 230 nM) in V79 Chinese hamster lung fibro blasts. The half-life for sequestration of LGE2 by covalent binding to cellular nucleophiles is at least an hour for 10 muM LG. This suggest s that the in vivo production and distribution of free LGs should be m easurable on this time scale. Following removal of the LGE2 and the re turn of the cultures to normal growth medium additional DNA-protein cr oss-links continued to form over the ensuing 6-24 h. The results sugge st that LG adducts to DNA or protein are not repaired, but react furth er at sites on protein or DNA in close proximity to the initial adduct s, forming cross-links in a slow phase of the process.