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

• Published in: International journal of cancer Vol. 120; no. 7; pp. 1396 - 1401
• Main Authors: Huang, Zhishan, Komninou, Despina, Kleinman, Wayne, Pinto, John T., Gilhooly, Elaine M., Calcagnotto, Ana, Richie, John P.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2007; Wiley-Liss
• Subjects: 4-Nitroquinoline-1-oxide - toxicity; 4‐nitroquinolin‐N‐oxide; Animal tumors. Experimental tumors; Animals; Biological and medical sciences; Carcinogens - toxicity; Carcinoma in Situ - chemically induced; Carcinoma in Situ - metabolism; Carcinoma in Situ - pathology; Epithelium - metabolism; Experimental head and neck tumors. Experimental orbital tumors; Focal Epithelial Hyperplasia - chemically induced; Focal Epithelial Hyperplasia - metabolism; Focal Epithelial Hyperplasia - pathology; glutathione; Glutathione - metabolism; Liver - drug effects; Male; Medical sciences; Neoplasm Proteins - metabolism; oral cancer; protein glutathiolation; Rats; Rats, Inbred F344; Sulfhydryl Compounds - metabolism; Tongue Neoplasms - chemically induced; Tongue Neoplasms - metabolism; Tongue Neoplasms - pathology; Tumors; Rat; Stomatology; Rodentia; Quinoline derivatives; Tongue cancer; Malignant tumor; Carcinogenesis; Protein; protein glutathiolation; Carcinogen; 4- nitroquinolin-N-oxide; Vertebrata; Mammalia; Cancerology; Animal; Oral cavity disease; oral cancer; Glutathione
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.22525

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 redox‐sensitive 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‐NQO‐treated 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.