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 or al OTZ on tumor and host tissue reduced GSH levels in fasting and radi ated models of GSH depletion, In addition, we studied the tumor's abil ity 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 OT Z (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), an d 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 bef ore and 18 hr following 1100 cGy of abdominal radiation and at 4 days, tumor, jejunal, and colonic mucosa were collected, Significant increa ses 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, jejun al, and colonic mucosa were collected from 8 animals, Oxoprolinase act ivity 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 co mpared to tumor following fasting and whole abdominal radiation, This increase does not appear to be due to a differential activity of oxopr olinase. OTZ may have a role in protection against toxicity associated with oxidative injury by selective repletion of normal host tissue GS H levels. (C) 1996 Academic Press, Inc.