Tryptophan metabolites in the urine of Turkish cows with urinary bladder cancer.

Industrial urinary bladder cancer in dye workers has been shown to be caused by exposure to certain aromatic amines (cf. 21 for review). Animal experiments have indicated that it is likely that the carcinogens are o-aminophenol metabolites (4, 5) and that these metabolites probably are carried to the urinary bladder by the urine (26, 41). Unidentified diazotizable aromatic amines in the urine of patients with spontaneous bladder cancer may also be responsible for this neoplastic disease, as suggested by Ekman and Str~imbeck (19). The known exogenous human bladder carcinogens (21) are chemically similar to several aromatic amines derived f rom tryptophan (14). The possible implication of tryptophan in bladder carcinogenesis was suggested by the findings of Dunning, Curtis, and Maun (18) and Dunning and Curtis (17), who showed that a high incidence of bladder tumors resulted when rats were fed ~-acetylaminofluorene combined with tryptophan or indole, while few bladder tumors were obtained with 2-acetylaminofluorene alone. Recently the mechanism of the carcinogenic activity of 2acetylaminofluorene on the bladder was suggested to be the increased urinary excretion of 3-hydroxykynurenine and 3-hydroxyanthranilic acid (39). This suggestion was based on the observation that feeding 2-acetylaminofluorene to rats for 2-6 days decreased the extent to which the livers of these animals converted 3-hydroxyanthranilic acid to quinolinic acid. Presumably 3-hydroxyanthranilic acid and 3-hydroxykynurenine would accumulate under these conditions, but no evidence was presented to show that these compounds do accumulate in rats fed ~-acetylaminofluorene (39). Recently the urinary excretion of t ryptophan metabolites by patients with and without neoplasms of the urinary bladder has been investigated (7, 10, 11). In one study (10) abnormally large quantities of kynurenine, hydroxykynurenine, acetylkynurenine, and kynurenic acid were excreted in the urine of about one half of a group of 41 patients with bladder cancer, especially after the administration of supplements of L-tryptophan, while the remaining patients excreted normal quantities of these and other t ryptophan metabolites before or after the ingestion of tryptophan supplements. In another study (7) it was reported that ten patients with bladder cancer excreted abnormally large quantities of anthranilic acid, hydroxyanthranilic acid, and hydroxykynurenine in the urine before and after the administration of 10 gm. of DL-tryptophan. Recently, a number of t ryptophan metabolites have been tested for carcinogenicity by implantation in the bladder of mice (1, 6). 3-Hydroxykynurenine, 3hydroxyanthranilic acid, the 8-methyl ether of xanthurenic acid, and 2-amino-3-hydroxyacetophenone were found to cause a significant number of tumors in mice (1). In the light of these findings, it was of interest to study the urinary excretion of t ryptophan metabolites by cows with bladder tumors as compared with normal cows. Neoplasms of the urinary bladder are very common in this species of animal and in water buffalo in certain districts of Turkey (30-32) and Formosa (20). This paper presents the results of quantitative measurement of t ryptophan metabolites in the urine of Turkish cows with bladder tumors as compared with normal cattle from the same area.