Interactions of prostaglandin A2 with the glutathione-mediated biotransformation system.

Abstract

The cyclopentenone prostaglandin A2 (PGA2) is known to inhibit cell proliferation, and metabolism of this compound thus might be important in controlling its ultimate function. The glutathione-related metabolism of PGA2 was therefore investigated both with purified glutathione S-transferase P1-1 (GSTP1-1) and with IGR-39 human melanoma cells. Firstly, the irreversible inhibition of human GSTP1-1 and its mutants C47S, C101S, and C47S/C101S was studied. PGA2 appeared to inhibit GSTP1-1 mainly by binding to the cysteine 47 moiety of the enzyme. This binding was reversed by a molar excess of GSH, indicating that retro-Michael cleavage occurs. Secondly, after exposing IGR-39 human melanoma cells to PGA2, both diastereoisomers of the PGA2-glutathione conjugate are excreted into the medium, although with a clear excess of the S-form, due to its preferential formation by the GSTP1-1 present in the cells. Thirdly, the effect of PGA2 on intracellular GST activity was determined by quantification of the excreted glutathione conjugate S-(2,4-dinitrophenyl)glutathione (DNPSG) after exposure to 1-chloro-2,4-dinitrobenzene. DNPSG excretion was inhibited after incubation with 10 or 20 microM PGA2 for 1 or 4 hr, as a result of glutathione depletion, reversible GST inhibition, and covalent modification of intracellular GST. Furthermore, PGA2 also inhibited transport of DNPSG by the multidrug resistance-associated protein, an effect that was reversible and competitive. In conclusion, PGA2 modulates all three aspects of the glutathione-mediated biotransformation system, i.e. GSH levels, GSTP1-1 activity, and transport of GSH conjugates. A role for GSTP1-1 as a specific transport protein inside the cell is indicated.

• Authors: M L van Iersel, N H Cnubben, N Smink, J H Koeman, P J van Bladeren
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 57 Issue 12 Pg. 1383-90 (Jun 15 1999) ISSN: 0006-2952 [Print] England
• PMID: 10353259 (Publication Type: Journal Article)

Chemical References

• Isoenzymes
• Prostaglandins A
• GSTP1 protein, human
• Glutathione S-Transferase pi
• Glutathione Transferase
• Glutathione
• prostaglandin A2

Topics

• Biotransformation
• Glutathione (metabolism)
• Glutathione S-Transferase pi
• Glutathione Transferase (antagonists & inhibitors, metabolism)
• Humans
• Isoenzymes (antagonists & inhibitors, metabolism)
• Melanoma
• Prostaglandins A (metabolism)
• Tumor Cells, Cultured