Formation of a prostaglandin A2-glutathione conjugate in L1210 mouse leukemia cells.

Prostaglandins containing a cyclopentenone moiety are potent antiviral and antigrowth compounds. Some evidence indicates that these prostaglandins are conjugated to glutathione by cells. However, the metabolism of one group, the prostaglandins of the A type, is unclear due to conflicting reports. We studied the uptake and metabolism of prostaglandin A2 (PGA2) in mouse L1210 leukemia and L929 fibroblast cell lines in which this prostaglandin has antiviral and antigrowth effects. Both cell types took up the PGA2 and then metabolized it to a more polar compound. Inside L1210 cells, PGA2 was initially conjugated to glutathione and then reduced at the 9-keto position to form 9-OH-PGA2-GSH. The 9-OH-PGA2-GSH was then secreted from the cells and apparently degraded to form the CysGly and Cys derivatives. Intracellular glutathione was decreased markedly by the addition of the PGA2 in L1210 and L929 cells. This result confirms that conjugation of PGA2 to glutathione occurs in both cell types. Formation of the 9-OH-PGA2-GSH and other glutathione-related conjugates was prevented when glutathione was depleted by growth in buthionine sulfoximine. The glutathione-depleted cells were insensitive to the cytotoxicity of the PGA2, suggesting that one of the glutathione-related conjugates may be involved in the cytotoxicity of PGA2. These results end the controversy over the metabolism of PGA2 and suggest mechanisms for its antiviral and antigrowth actions.