Selective glutathione repletion with oral oxothiazolidine carboxylate (OTZ) in the radiated tumor-bearing rat.
Oxothiazolidine carboxylate (OTZ) is a cysteine prodrug which augments intracellular glutathione (GSH) levels. We examined the effects of oral OTZ on tumor and host tissue reduced GSH levels in fasting and radiated models of GSH depletion. In addition, we studied the tumor's ability to utilize OTZ via the enzyme, oxoprolinase. Fischer 344 rats (n = 40) were implanted with MCA sarcoma and studied at 10% tumor burden. Treatment consisted of 10 mmol/kg OTZ or buffer orally. After a 24-hr fast, 16 animals were treated and tumor, kidney, jejunal, and colonic mucosa were collected after 4 hr. Significant increases in GSH with OTZ (n = 8) vs buffer (n = 8) were seen in kidney (5.6 +/- 0.4 vs 4.3 +/- 0.9; P < 0.01), jejunum (13.8 +/- 1.3 vs 12.1 +/- 1.1; P < 0.05), and colon (6.7 +/- 1.2 vs 5.3 +/- 0.6; P < 0.05), but not tumor (8.9 +/- 2.4 vs 10.6 +/- 1.4; P = 0.12). Sixteen animals were treated 4 hr before and 18 hr following 1100 cGy of abdominal radiation and at 4 days, tumor, jejunal, and colonic mucosa were collected. Significant increases in GSH with OTZ (n = 8) vs buffer (n = 8) were noted in jejunum (9.3 +/- 1.1 vs 7.5 +/- 1.8; P < 0.05) and colon (5.6 +/- 1.1 vs 4.3 +/- 0.9; P < 0.05) but not tumor (8.4 +/- 1.6 vs 7.6 +/- 1.4; P = 0.34). To determine tissue oxoprolinase activity, tumor, kidney, liver, jejunal, and colonic mucosa were collected from 8 animals. Oxoprolinase activity was highest in the kidney (814 +/- 145) with no difference noted between liver and tumor (280 +/- 117 and 324 +/- 137, respectively). Oral OTZ selectively increases reduced GSH levels in normal tissues compared to tumor following fasting and whole abdominal radiation. This increase does not appear to be due to a differential activity of oxoprolinase. OTZ may have a role in protection against toxicity associated with oxidative injury by selective repletion of normal host tissue GSH levels.
Rose
D M
DM
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.
Hochwald
S N
SN
Harrison
L E
LE
Burt
M
M
D000284:Administration, Oral; D000818:Animals; D005978:Glutathione / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008297:Male; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000627:therapeutic use; D011752:Pyroglutamate Hydrolase / Q000378:metabolism; D011761:Pyrrolidonecarboxylic Acid; D011837:Radiation-Protective Agents / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D013844:Thiazoles / Q000627:therapeutic use*; D053778:Thiazolidines; D014018:Tissue Distribution
D011355:Prodrugs; D011837:Radiation-Protective Agents; D013844:Thiazoles; D053778:Thiazolidines; D011752:Pyroglutamate Hydrolase; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid; C029536:2-oxothiazolidine-4-carboxylic acid