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

Division of Pathology, National Institute of Health Sciences, Tokyo, Japan

Kazuhiro Toyoda

Division of Pathology, National Institute of Health Sciences, Tokyo, Japan

Makoto Shibutani

Division of Pathology, National Institute of Health Sciences, Tokyo, Japan, shibutan{at}nihs.go.jp

Naoko Niho

Division of Pathology, National Institute of Health Sciences, Tokyo, Japan

Chikako Uneyama

Division of Pathology, National Institute of Health Sciences, Tokyo, Japan

Noriyuki Takahashi

Division of Pathology, National Institute of Health Sciences, Tokyo, Japan

Masao Hirose

Division of Pathology, National Institute of Health Sciences, Tokyo, Japan

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.

Key Words: Isothiocyanates • metabolites • urinary bladder • cytotoxicity • F344 rat.

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