Evaluation of isothiocyanates as potent inducers of carcinogen-detoxifying enzymes in the urinary bladder: critical nature of in vivo bioassay

• Published in: Nutrition and cancer Vol. 54; no. 2; pp. 223 - 231
• Main Authors: Munday, R, Zhang, Y, Fahey, J.W, Jobson, H.E, Munday, C.M, Li, J, Stephenson, K.K
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA Lawrence Erlbaum Associates, Inc 01.01.2006; Taylor& Francis
• Subjects: animal disease models; Animals; antinutritional factors; bioassays; Biological and medical sciences; Biological Assay; bladder diseases; carcinogenesis; carcinogens; Enzyme Induction - drug effects; enzymes; Epidemiology; Female; glutathione transferase; Glutathione Transferase - drug effects; Glutathione Transferase - metabolism; Glutathione Transferase - urine; human diseases; in vivo studies; Inactivation, Metabolic; isothiocyanates; Isothiocyanates - chemistry; Isothiocyanates - pharmacology; Isothiocyanates - urine; Medical sciences; metabolic detoxification; neoplasms; Other treatments; oxidoreductases; quantitative structure-activity relationships; Quinone Reductases - drug effects; Quinone Reductases - metabolism; Quinone Reductases - urine; Rats; Rats, Sprague-Dawley; risk factors; Treatment. General aspects; Tumor Cells, Cultured; Tumors; Urinary Bladder - drug effects; Urinary Bladder - enzymology; Urinary Bladder Neoplasms - prevention & control; Carcinogen; Evaluation; In vivo; Enzyme inducer; Urinary system; Nutrition; Urinary bladder
• ISSN: 0163-5581; 1532-7914
• DOI: 10.1207/s15327914nc5402_9

Deficiency of carcinogen-detoxifying phase 2 enzymes, such as glutathione S-transferase (GST) and NAD(P)H:quinone oxidoreductase 1 (NQO1), increases bladder cancer risk in humans. We report that several isothiocyanates (ITCs) that have not been previously examined, 1-methylbutyl ITC in particular, potently and preferentially induce both GST and NQO1 in the rat bladder. Comparison of 25 ITCs that are closely related in chemical structures showed that a 3-5-carbon aliphatic side chain with a methyl group attached to the alpha carbon was crucial for maximal inducer activity in the bladder. Surprisingly, cell-based bioassays failed to predict the phase 2 enzyme-inducing activity of the ITCs in the bladder. Furthermore, although ITCs are principally metabolized in vivo to dithiocarbamates (DTCs), which are believed to serve as the carriers of ITCs and are rapidly eliminated and concentrated in the urine, the total urinary levels of ITC plus DTC did not correlate with the degree of GST and NQO1 induction by the ITCs in the bladder of rats. Thus, several underappreciated ITCs are exceedingly potent inducers of GST and NQO1 in the rat bladder but were predicted neither by in vitro bioassays of phase 2 enzyme induction nor by their appearance or concentration in urine in vivo.