Intracellular glutathione level modulates the induction of apoptosis by Delta(12)-prostaglandin J(2)

We studied the effect of intracellular glutathione (GSH), which was known to conjugate readily with an alpha,beta-unsaturated carbonyl of 9-deoxy-Delta(9,12)-13,14-dihydroPGD(2) (Delta(12)-PGJ(2)), on the cytotoxicity of Delta(12)-PGJ(2). Delta(12)-PGJ(2) caused DNA fragmentation in human hepatocellular carcinoma Hep 3B cells, which was blocked by cycloheximide (CHX). The Delta(12)-PGJ(2)-induced apoptosis was augmented by GSH depletion resulted from pretreatment with buthioninine sulfoximine (BSO), an inhibitor of gamma-glutamylcysteine synthetase. On the contrary, N-acetyl-cysteine (NAC), a precursor of cysteine, elevated the GSH level and protected cells from initiating apoptosis by Delta(12)-PGJ(2). Sodium arsenite, a thiol-reactive agent, also induced apoptosis, which was potentiated or attenuated by BSO or NAC treatment respectively These results suggest that the apoptosis-inducing activity of Delta(12)-PGJ(2) is due to thiol-reactivity and intracellular GSH modulates the Delta(12)-PGJ(2)-induced apoptosis by regulating the accessibility of Delta(12)-PGJ(2) to target proteins containing thiol groups.