Comparison of phenethyl and 6-phenylhexyl isothiocyanate-induced toxicity in rat esophageal cell lines with and without glutathione depletion.
Phenethyl isothiocyanate (PEITC) and its synthetic homolog, 6-phenylhexyl isothiocyanate (PHITC), are both potent inhibitors of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung mice tumorigenesis. However, unlike PEITC, PHITC enhanced N-nitrosomethylbenzylamine (NMBA)-induced rat esophageal tumorigenesis. These findings imply that due to its unique chemical properties, PHITC's effects on esophageal cells are procarcinogenic rather than chemopreventive. Relative to PEITC, PHITC is more lipophilic and less reactive, which could result in higher PHITC intracellular levels. Due to ITCs' inherently high level of thiol reactivity, increased intracellular levels of PHITC have the potential to deplete intracellular glutathione (GSH) reserves. Since GSH is a primary intracellular antioxidant and cytoprotective enzyme cofactor, preservation of intracellular GSH status is crucial for cytoprotection. Despite the recognized importance of isothiocyanate structure with the potential for toxicity, no studies have yet investigated the association between the primary intracellular free thiol, GSH, and isothiocyanate-induced toxicity in this target cell population. The present study investigated whether PEITC and PHITC display unique cytotoxic profiles in cultured rat esophageal cells, and also monitored the effects of ITC challenge on cellular GSH status. A final series of experiments investigated the converse i.e., affects of modulation of intracellular GSH status on ITC-mediated toxicity. Dose-response curves revealed that PEITC was significantly more toxic in tumorigenic and non-tumorigenic cells relative to PHITC. The ITC-GSH interaction studies demonstrated comparable GSH levels following either PEITC or PHITC challenge, and also showed that GSH depletion did not augment ITC-mediated cellular toxicity. While our data demonstrate structure related differences in ITC-mediated cytotoxicities, these differences do not appear to be directly attributable to cellular GSH pools.
Hudson
Tamaro S
TS
Division of Cancer Prevention, Cancer Prevention Fellowship Program, National Cancer Institute, National Institute of Health, Bethesda, MD 20892, USA.
Stoner
Gary D
GD
Morse
Mark A
MA
Young
Heather
H
Mallery
Susan R
SR
D000818:Animals; D002273:Carcinogens / Q000633:toxicity*; D002460:Cell Line; D002470:Cell Survival; D005978:Glutathione / Q000172:deficiency* / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D005980:Glutathione Reductase / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D017879:Isothiocyanates / Q000633:toxicity*; D051381:Rats
D002273:Carcinogens; D007527:Isoenzymes; D017879:Isothiocyanates; C073279:6-phenylhexyl isothiocyanate; C058305:phenethyl isothiocyanate; D005979:Glutathione Peroxidase; D005980:Glutathione Reductase; D007041:Hypoxanthine Phosphoribosyltransferase; D005982:Glutathione Transferase; D005978:Glutathione