Formation of a prostaglandin A 2-glutathione conjugate in L1210 mouse leukemia cells

Abstract

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 A 2 (PGA 2) in mouse L1210 leukemia and L929 fibroblast cell lines in which this prostaglandin has antiviral and antigrowth effects. Both cell types took up the PGA 2 and then metabolized it to a more polar compound. Inside L1210 cells, PGA 2 was initially conjugated to glutathione and then reduced at the 9-keto position to form 9-OH-PGA 2-GSH. The 9-OH-PGA 2-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 PGA 2 in L1210 and L929 cells. This result confirms that conjugation of PGA 2 to glutathione occurs in both cell types. Formation of the 9-OH-PGA 2-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 PGA 2, suggesting that one of the glutathione-related conjugates may be involved in the cytotoxicity of PGA 2. These results end the controversy over the metabolism of PGA 2 and suggest mechanisms for its antiviral and antigrowth actions.