Effects of gamma-Glutamylcysteine Ethyl Ester in Cisplatin-Induced Changes in Prostanoid Concentrations in Rat Gastric and Colonic Mucosa

Abstract

We evaluated changes in gastric and colonic mucosal prostanoid contents in rats treated with cisplatin. We also determined effects of gamma-glutamylcysteine ethyl ester (GCE), a pro-drug of glutathione, on cisplatin-induced changes in prostanoid concentrations. Rats were divided into three groups--the control: 0.5 ml of physiological saline was administered intraperitoneally (i.p.); the cisplatin group: 0.5 ml of cisplatin, 10 mg/kg, was administered i.p.; the GCE + cisplatin group: GCE, 30 min before cisplatin injection. In each group, rat gastric and colonic mucosa were isolated and their prostanoid concentrations were determined using high-performance liquid chromatography. 6-Keto-PGF1 alpha, PGF2 alpha, PGE2 were detected in gastric mucosa. In addition to these prostaglandins (PGs), thromboxane (TX) B2 was also detected in the colonic mucosa. In the cisplatin group, gastric mucosal 6-keto-PGF1 alpha concentration decreased significantly 24 h after administration, while PGE2 and PGD2 concentrations were increased significantly after 12 and 24 h, respectively. In colonic mucosa, cisplatin increased PGE2 and PGD2 concentrations, while it decreased TXB2 concentration. 6-Keto-PGF1 alpha concentration was not affected by cisplatin in colonic mucosa. GCE canceled out these changes in prostanoid concentrations in both gastric and colonic mucosa. Changes in prostanoid concentrations might be implicated in the adverse gastrointestinal effects of cisplatin, and clinical application of GCE could be expected.

Evidence for a Re-Evaluation of the Neurochemical and Anatomical Bases of Chemotherapy-Induced Vomiting

“…The cysteinyl leukotriene LTC 4 , by virtue of its glutathione moiety, can bind to the same solute-carrier membrane transporter that binds glutathione-conjugated platinum, a key cellular metabolite of cisplatin and the other platinum-based chemotherapies. , This competitive interaction has been exploited in experiments using LTC 4 treatment to successfully enhance the tumor-killing potency of cisplatin in glioma cells, demonstrating that cisplatin resistance in cancer cells is at least partially mediated by active removal of the platinum−glutathione conjugate from the cell. , Essentially no work has been done studying this interaction with regard to the gastrointestinal tract, although some data have been acquired with regard to eicosanoids, cisplatin, and emesis. Indeed, one study found that pretreatment with a glutathione prodrug prior to cisplatin treatment could abolish the rise in GI prostaglandin activity associated with cisplatin and vomiting in general. It is possible the high glutathione levels caused increased production of glutathione-conjugated, nonemetogenic prostaglandin metabolites (e.g., PGJ 2 ) and shifted the metabolic balance away from production of the pro-emetic prostaglandin metabolites (PGE 2 or F 2 α).…”

“…389,391 Essentially no work has been done studying this interaction with regard to the gastrointestinal tract, although some data have been acquired with regard to eicosanoids, cisplatin, and emesis. Indeed, one study 392 found that pretreatment with a glutathione prodrug prior to cisplatin treatment could abolish the rise in GI prostaglandin activity associated with cisplatin and vomiting in general. It is possible the high glutathione levels caused increased production of glutathione-conjugated, nonemetogenic prostaglandin metabolites (e.g., PGJ 2 ) and shifted the metabolic balance away from production of the pro-emetic prostaglandin metabolites (PGE 2 or F 2 R).…”

The antiemetic interaction of Δ9-tetrahydrocannabinol when combined with tropisetron or dexamethasone in the least shrew

“…Depending on the emetogen, different neurochemical systems are involved, although several key neurotransmitters are stimulated in common. CIV is not produced via a single specific neurotransmitter, but by the release of various emetogenic signals including serotonin, substance P (SP), dopamine, and prostaglandins (Goto et al, 1998; Kasabdji et al, 1996; Saito et al, 1999; Veyrat-Follet et al, 1997). …”