Stereoselective Conjugation of Prostaglandin A2 and Prostaglandin J2 with Glutathione, Catalyzed by the Human Glutathione S-Transferases A1-1, A2-2, M1a-1a, and P1-1

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• 作者：Jan J. P. Bogaards ; Joke C. Venekamp ; and Peter J. van Bladeren
• 刊名：Chemical Research in Toxicology
• 出版年：1997
• 出版时间：March 1997
• 年：1997
• 卷：10
• 期：3
• 页码：310 - 317
• 全文大小：277K
• 年卷期：v.10,no.3(March 1997)
• ISSN：1520-5010

文摘

Prostaglandins containing an ,-unsaturated ketogroup, such as prostaglandin A₂(PGA₂)and prostaglandin J₂ (PGJ₂), inhibit cellproliferation. These cyclopentenone prostaglandinsmay be conjugated with GSH chemically or enzymatically via glutathioneS-transferases, andthis has been suggested to result in inhibition of theantiproliferative mode of action. In thepresent study, the role of the major human GSTs in the conjugation ofPGA₂ and PGJ₂ withGSH was investigated with purified enzymes, i.e.,the Alpha-class enzymes GST A1-1 andGST A2-2, the Mu-class enzyme GST M1a-1a, and the Pi-class enzyme GSTP1-1. The GSHconjugates were separated from the parent compound by HPLC andidentified by fast atombombardment mass spectrometry and ¹H-NMR. Two GSHconjugates were found for bothPGA₂ and PGJ₂, the R- andS-GSH conjugates of both prostaglandins. Incubationexperimentswith PGA₂ and PGJ₂ (70-600 M) clearlyshowed the role of individual GSTs in the conjugationof PGA₂ and PGJ₂. Compared to the chemicalreaction, enzyme activities towards PGA₂ wereup to 5.4 times as high (GSTA1-1) at the lowest concentration (70M), while at the highestconcentration (600 M) enzyme activities were up to 3.0 times as high(GST P1-1). For PGJ₂,enzyme activities were up to 4.3 (GSTM1a-1a, 70 M) and up to 3.1(GSTM1a-1a, 600 M)times as high. As expected, similar amounts of the R-and S-conjugates of both prostaglandinswere found in the chemical reaction. Striking stereoselectivitiesin conjugating activities wereobserved for GST A1-1 and GST P1-1. GST A1-1 favors the formationof the R-GSH conjugatesof both prostaglandins. GST P1-1 showed a clear selectivity withregard to the formation ofthe S-GSH conjugate of PGA₂. However, thisselectivity was not found for the formation ofthe S-GSH conjugate of PGJ₂. GSTM1a-1ashowed no stereoselectivity with regard to theGSH conjugation of both PGA₂ and PGJ₂.GSTA2-2 only showed some minor formation of theR-GSH conjugate of PGJ₂. The possibleimplications of the observed stereoselectivity on theeffects of PGA₂ and PGJ₂ arediscussed.