Toxic Effects of Benzyl and Allyl Isothiocyanates and Benzyl-Isoform Specific Metabolites in the Urinary Bladder After a Single Intravesical Application to Rats

Abstract

Allyl isothiocyanate (AITC) is known to be weakly carcinogenic, whereas benzyl isothiocyanate (BITC) has been suggested to exert carcinogenicity toward the rat urinary bladder. To elucidate direct toxic effects of isothiocyanates (ITCs), BITC, AITC, or BITC-metabolites conjugated either with glutathione, cysteinylglycine, cysteine, or mercapturic acid were intravesically instilled into female F344 rats. Exposure to AITC and BITC at 2.8 mg/kg body weight, and the same mol quantity (37 μ mol/kg) of BITC-metabolites was for 2 h. Nineteen hours thereafter, the animals were intravenously administered 5-bromo-2'-deoxyuridine (BrdU) and killed 1 h later. BITC caused more profound toxic damage than AITC. Among the BITC-metabolites, cytotoxicity was evident with intermediate glutathione or cysteinylglycine conjugates, whereas the mercapturic acid, considered to be the major final urinary metabolite, exerted little effects. BrdU labeling was essentially dependent on the degree of cytotoxic potential of each compound. Considering the previous study results demonstrating the generation of free BITC from metabolites in urine, the present results support the idea that cytotoxic activity of orally administered ITCs is derived from free forms cleaved from conjugated metabolite(s) in urine.

Keywords

Isothiocyanates metabolites urinary bladder cytotoxicity F344 rat.

References

Bollard M. , Stribbling S. , Mitchell S. , Caldwell J. (1997). The disposition of allyl isothiocyanate in the rat and mouse. Food Chem Toxicol 35: 933—943.

Bruggeman IM , Temmink, JHM , Van Bladeren PJ (1986). Glutathione- and cysteine-mediated cytotoxicity of allyl and benzyl isothiocyanate . Toxicol Appl Pharmacol 83: 349—359.

Brüsewitz G. , Cameron BD , Chasseaud LF , Gorler K. , Hawkins DR , Koch H. , Mennicke WH (1977). The metabolism of benzyl isothiocyanate and its cysteine conjugate. Biochem J 162: 99—107.

Dunnick JK , Prejean JD , Haseman J. , Thompson RB , Giles HD , McConnell EE (1982). Carcinogenesis bioassay of allyl isothiocyanate . Fundam Appl Toxicol 2: 114—120.

Hirose M. , Yamaguchi T. , Kimoto N. , Ogawa K. , Futakuchi M. , Sano M. , Shirai T. (1998). Strong promoting activity of phenylethyl isothiocyanate and benzyl isothiocyanate on urinary bladder carcinogenesi s in F344 male rats. Int J Cancer 77: 773—777.

Ioannou YM , Burka LT , Matthews HB (1984). Allyl isothiocyanate: comparative disposition in rats and mice. Toxicol Appl Pharmacol 75: 173—181.

Kasamaki A. , Yasuhara T. , Urasawa S. (1987). Neoplastic transformation of Chinese hamster cells in vitro after treatment with flavoring agents. J Toxicol Sci 12: 383—396.

Kassie F. , Knasmüller S. (2000). Genotoxic effects of allyl isothiocyanate (AITC) and phenethyl isothiocyanate (PEITC). Chem Biol Interact 127: 163—180.

Musk SRR , Johnson IT (1993). The clastogenic effects of isothiocyanates. Mutation Res 300: 111—117.

10.

Musk SRR , Astley SB , Edwards SM , Stephenson P. , Hubert RB , Johnson IT (1995). Cytotoxic and clastogenic effects of benzyl isothiocyanate towards cultured mammalian cells. Food Chem Toxicol 33: 31—37.

11.

National Toxicology Program (1982). NTP technical report on the carcinogenesis bioassay of allyl isothiocyanate, NIH Publication 83—1790. U.S. Department of Health and Human Services, Washington, DC.

12.

Neudecker T. , Henschler D. (1985). Allyl isothiocyanate is mutagenic in Salmonella typhimurium. Mutat Res 156: 33—37.

13.

Ogawa K. , Hirose M. , Cui L. , Sugiura S. , Chen X. , Shirai T. (in press). Dose dependent promotion effect of phenylethy l isothiocyanate in the two-stage rat urinary bladder and liver carcinogenesis. Nutr Cancer.

14.

Tookey HL , Van Etten CH , Daxenbichler ME (1980). Glucosinolates, In: Toxic Constituents of Plant Foodstuffs (2nd ed), Liener IE (ed). Academic Press, New York, pp 103—142.

15.

Yamaguchi T. (1980). Mutagenicity of isothiocyanates, thiocyanates and thioureas on Salmonella typhimurium. Agric Biol Chem 44: 3017— 3018.

16.

Zhang Y. , Talalay P. (1994). Anticarcinogenic activities of organic isothiocyanates: chemistry and mechanisms. Cancer Res 54(Suppl): 1976s— 1981s.