1. Effects of glutathione isopropyl ester on bile flow in glutathione-depleted rats
H Yoshida, T Harada, Y Kuronuma, M Iijima, T Tamano Arch Int Pharmacodyn Ther . 1993 Mar-Apr;322:105-14.
Combined administration of buthionine sulfoximine (2.5 mmol/kg, i.p.) and diethyl maleate (1.0 ml/kg, i.p.) resulted in a near-complete depletion of hepatic glutathione (0.02 mumol/g liver vs 5.17 mumol/g in saline-treated controls) in male Sprague-Dawley rats. Bile flow was markedly reduced in the rats as compared with the controls and glutathione was not detected in the bile. The linear regression of the correlation between bile flow and endogenous bile-acid excretion rates revealed that no bile acid-independent bile flow was produced in the glutathione-depleted rats. The bile flow was partially restored by an intravenous infusion of glutathione isopropyl ester (1.17 mmol/kg/hr). Glutathione levels were increased in the bile (16 nmol/kg/min) and in the liver (0.55 mumol/g) at the end of the 100 min infusion period of the ester. The increments in bile flow rates were not proportional to the biliary excretion rates of bile acids or glutathione, and the flow rates suddenly increased when glutathione levels in the bile reached an apparent threshold. The increments, not accompanied with an excretion of diethyl maleate-glutathione conjugate, were much greater than expected from the osmotic choleresis of glutathione in the bile. These results indicate that hepatic glutathione above a certain level is required for the formation of a portion of bile flow, and that an intravenous administration of glutathione isopropyl ester is effective in partially restoring the bile formation impaired by glutathione depletion.
2. Glutathione isopropyl ester reduces UVB-induced skin damage in hairless mice
S Kobayashi, C Tohyama, M Takehana Photochem Photobiol . 1996 Jan;63(1):106-10. doi: 10.1111/j.1751-1097.1996.tb02999.x.
The protective effect of administration of glutathione (GSH) isopropyl ester on photodamage, such as lipid peroxidation, inflammation and tumorigenesis induced by UV exposure (290-400 nm, max. 312 nm), was investigated using hairless mice. Pretreatment with 20 mg/kg GSH isopropyl ester prevented the increases of thiobarbituric acid-reactive substance (TBARS) formation in skin and serum sialic acid, indices of lipid peroxidation and inflammatory reaction, respectively, which were caused by a single dose (15 kJ/m2) of UV irradiation. The level of epidermal GSH in skins of the GSH ester-treated mice was maintained within normal limits. When mice were exposed to UV at a dose of 2 kJ/m2, three times weekly, skin tumors developed in all of them after 25 weeks. The formation of skin tumors was significantly inhibited by administration of 10 mg/kg GSH ester prior to each UV irradiation for 25 weeks. Moreover, the increases of cutaneous TBARS and serum sialic acid in the tumor-bearing mice were also prevented by continuous pretreatment with GSH ester. Even after 24 weeks, the epidermal GSH content of the pretreated mice was mostly retained compared to nonirradiated mice. However, administration of GSH prior to acute or chronic UV irradiation had no effect on the UV-induced damage. The present results suggest that the protection from photodamage afforded by pretreatment with GSH ester is due to maintenance of a normal GSH level.
3. Protective actions of YM737, a new glutathione analog, against cerebral ischemia in rats
M Yamamoto, K Hidaka, N Sakamoto, K Noguchi, A Iwai, S Yatsugi, T Yuasa Res Commun Chem Pathol Pharmacol . 1993 Aug;81(2):221-32.
Effects of YM737[N-(N-r-L-glutamyl-L-cysteinyl)glycine 1-isopropyl ester sulfate monohydrate], a new glutathione (GSH) analog more readily transported into cells than GSH, on cerebral ischemia were compared with those of GSH and some other drugs in rats subjected to occlusion of the bilateral carotid arteries. YM737 significantly reduced lethality, increased brain-water levels as measured by both dry-wet and NMR methods, and increased malondialdehyde (MDA) levels in the cerebral ischemic rats. On the other hand, pharmacological actions of GSH itself was less than those of YM737. In the ischemic rats used in the present study, there was no significant difference in 31P-NMR signals between the normal and the cerebral ischemic rats. These results suggest that YM737 showed anti-cerebral ischemic effects presumably due, in part, to inhibition of lipid peroxidative responses.