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.