Inhibition of GSH-dependent PGH2 isomerase in mammary adenocarcinoma cells by allicin.
We have reported that allicin, a constituent of garlic oil, has no effect on the activities of platelet cyclooxygenase or thromboxane synthase, or vascular PGI2 synthase. The effect of allicin on glutathione (GSH) dependent PGH2 to PGE2 isomerase is unknown. We therefore studied the effect of allicin on PGE2 biosynthesis in a murine mammary adenocarcinoma cell line (No 4526). Intact or sonicated cells were incubated with either 14C-arachidonic acid (AA) or 14C-PGH2, respectively. Following metabolism, products were extracted, separated by TLC and analyzed by radiochromatographic scan. PGE2 was predominantly formed with minimal amounts of PGF2 alpha and PGD2. Formation of 6-keto-PGF1 alpha or TXB2 was not detected indicating the absence of TXA2 and PGI2 synthase activity. Indomethacin and ibuprofen inhibited the PGE2 formation (p less than 0.05). The enzymatic PGE2 formation in sonicates was blocked by depletion of the cellular non-protein thiols by buthionine sulfoximine and was shown to be dependent on GSH. Allicin, over the range of 10-1000 microM, inhibited the formation of PGE2 in cells exposed to 2.0 microM 14C-AA for 20 min. and in sonicated cells incubated with 20.0 microM 14C-PGH2 for 2 min (p less than 0.05). Allicin did not alter cyclooxygenase-mediated oxygen utilization in ram seminal vessicle microsomes, suggesting that allicin selectively inhibits the GSH-dependent PGH2 to PGE2 isomerase in this adenocarcinoma cell line.
Shalinsky
D R
DR
Dept. of Pharmacology, Tulane Univ. School of Medicine, New Orleans, LA 70112.
McNamara
D B
DB
Agrawal
K C
KC
D000230:Adenocarcinoma / Q000201:enzymology*; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D004220:Disulfides; D005978:Glutathione / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases; D007535:Isomerases / Q000037:antagonists & inhibitors*; D007700:Kinetics; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008861:Microsomes / Q000201:enzymology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism; D044262:Prostaglandin H2; D000071876:Prostaglandin-E Synthases; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011463:Prostaglandins H / Q000378:metabolism; D012669:Seminal Vesicles / Q000187:drug effects / Q000201:enzymology; D012756:Sheep; D013441:Sulfinic Acids / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D001095:Arachidonic Acids; D004220:Disulfides; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D013441:Sulfinic Acids; D016718:Arachidonic Acid; C006452:allicin; D044262:Prostaglandin H2; D011451:Prostaglandin-Endoperoxide Synthases; D007535:Isomerases; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D005978:Glutathione; D015232:Dinoprostone