Enhanced levels of glutathione and protein glutathiolation in rat tongue epithelium during 4‐NQO‐induced carcinogenesis

Abstract

High glutathione (GSH) levels are commonly found in oral tumors and are thought to play an important role in tumorigenesis. While posttranslational binding of GSH to cellular proteins (protein glutathiolation) has recently been recognized as an important redoxsensitive regulatory mechanism, no data currently exist on this process during carcinogenesis. Our goal was to determine the effects of 4-nitroquinoline-N-oxide (4-NQO)-induced carcinogenesis on tongue levels of protein-bound and free GSH and related thiols in the rat. Male F-344 rats (6 weeks of age) were administered either 4-NQO (20 ppm) in drinking water or tap water alone (controls) for 8 weeks. Twenty-four weeks after cessation of 4-NQO, squamous cell carcinomas of the tongue were observed in all rats. The levels of both free and bound GSH in tumors, as well as in adjacent tissues, were 2-to 3-fold greater than in tongue epithelium from control rats (p < 0.05). Prior to tumor formation, at 8 weeks after cessation of 4-NQO, hyperplasia, dysplasia and carcinoma in situ were observed in 100%, 25% and 12.5% of 4-NQOtreated rats, respectively. At this early stage of carcinogenesis, levels of free and bound GSH were increased 50% compared with tongue tissues from control rats (p < 0.05). Glutathione disulfide (GSSG) levels were also 2-fold greater in tongue tissues from 4-NQO treated vs. control rats (p < 0.05). Altogether, these results suggest that protein glutathiolation, together with GSH and GSSG levels, are induced during oral carcinogenesis in the rat possibly as a result of enhanced levels of oxidative stress. ' 2006 Wiley-Liss, Inc.

Nitroaromatic compounds: Environmental toxicity, carcinogenicity, mutagenicity, therapy and mechanism

“…A goal was to determine the effects of 4-NQO-induced carcinogenesis on tongue levels of protein-bound and free GSH and related thiols in the rat (Huang et al, 2007). Results suggest that protein glutathionylation, together with GSH and oxidized GSH levels, are induced during oral carcinogenesis in the rat, possibly as a result of enhanced levels of OS.…”

Association of Selenium Status and Blood Glutathione Concentrations in Blacks and Whites

“…GSH is a first line of defense against oxidative stress (25), and decreased GSH can result in increased risk for cancer (26). Glutathionylated proteins (GSSP) are major products of GSH oxidation, and their formation represents a potential mechanism by which oxidative stress can impact carcinogenesis (27,28). In healthy adult men, we observed that supplementation with selenium-enriched yeast (247 μg/d) resulted in a progressive increase in GSH and decrease in glutathionylated proteins in blood over 9 months (29).…”

Blood Iron, Glutathione, and Micronutrient Levels and the Risk of Oral Cancer

“…Oxidative stress may be the critical factor that links low body iron stores, riboflavin status and GSH levels with increased risk for oral cancer. Oxidative stress has been associated with iron deficiency in numerous studies [21][22][23] and is thought to be an important contributor to oral carcinogenesis [24][25][26][27] . As described above, GSH represents the major intracellular antioxidant and maintenance of its levels is dependant upon riboflavin, which, through its metabolite FAD, serves as a key co-factor for the enzyme, glutathione reductase, responsible for maintaining GSH in its reduced state 84 .…”

“…Increased levels of oxidative stress have been associated with iron deficiency anemia in numerous studies and is thought to contribute to the pathogenesis of patients with this disorder [21][22][23] . Oxidative stress has also been linked to the development of oral cancer [24][25][26][27] and diets high in antioxidant/ nutrients have been associated with reduced risk for oral cancer whereas increased risk has been associated with low fruit intake 28 and low intake and serum levels of β-carotene, selenium, vitamin A, α-tocopherol, ascorbic acid and lycopene 29,30 In chemoprevention trials of oral premalignancies and cancer, several of these micronutrient antioxidants exhibited antiproliferative effects but data on recurrence is more limited 31 .…”