The Concentration of Free and Conjugated 3-Hydroxyanthranilic Acid in the Urine of Bladder Tumour Patients Before and After Therapy, Measured with an Enzymatic Method

Abstract

Summary.-The basal concentration of the tryptophan metabolite 3-hydroxyanthranilic acid (30HA), which has carcinogenic properties, was measured with an enzymatic method of determination which allowed separate measurement of free and conjugated 30HA. The concentration of free 30HA in untreated bladder cancer patients was significantly (P < 0.001) higher than in a healthy control group, but after local therapy the concentration was significantly lower than before treatment (P < 0-01). The concentration of conjugated 30HA was nearly constant in the three groups. It was concluded that other factors than a genetic determined abnormality might be operating in bladder cancer patients which could lead to an abnormal concentration of 30HA in their urine.'rHE role of tryptophan metabolites in the aetiology of human urinary bladder cancer has been the subject of numerous investigations. Twenty-two years ago a relationship was suggested by Dunning, Curtis and Maun (1950), who showed that a high incidence of bladder tumours resulted when rats were fed 2-acetylaminofluorene combined with DL-tryptophan. Several primary aromatic amine tryptophan metabolites, with a structure similar to known environmental human bladder carcinogens, are present in human urine (Brown and Price, 1956). Direct application to the mouse bladder of these metabolites by the " pellet technique " confirmed the carcinogenic activity of several of them (Bryan, 1971). Recently, Radomski, Glass and Deichmann (1971) have given evidence supporting the role of tryptophan in bladder carcinogenesis by feeding 7 times the normal daily intake of DL-tryptophan to beagle dogs for periods of 3 5 months to 7 years. Marked local hyperplasia of the transitional bladder epithelium was observed in all cases.Several clinical studies of the metabolism of tryptophan have been carried out in patients with bladder cancer (Brown et al., 1960;Price and Brown, 1962;Benassi, Perissinotto and Allegri, 1963;Kochen and Hochberg, 1970). In these investigations one or more metabolites were determined in samples of 24-hour urine. In most of the studies, loading with an oral dose of L-tryptophan was necessary because the analytical methods are working at lower limits of detection and sensitivity when used on basal urines. Because of the differences in method, it is difficult to compare the results obtained in the different laboratories. An abnormal metabolism was often observed in patients with spontaneous bladder cancer, but in other pathological conditions an abnormal excretion pattern was also found (Rose,.Moreover, the excretion of metabolites is related to tryptophan intake, hormonal regulation of the pathway, intake levels of pyridoxine and metabolic individualitv (Albanese et al., 1972). In a pilot study

Presence of 3‐Hydroxyanthranilic Acid in Rat Tissues and Evidence for Its Production from Anthranilic Acid in the Brain

“…3-HANA has long been known as an integral link in the kynurenine pathway, the primary route of tryptophan degradation in mammalian cells. Because of its possible role in the pathogenesis of bladder cancer (Boyland and Williams, 1956;Benassi et al, 1963;Teulings et al, 1973), which has been speculatively related to its ability to interfere with mitochondria1 oxidative phosphorylation (Quagliariello et al, 1964), 3-HANA received substantial attention from researchers in the 1950s and 1960s (Gorrod et al, 1967). Studies focussed on the disposition of the substance in urine where 3-HANA occurs in both conjugated and free forms (Brown and Price, 1956;Price et al, 1965), and on the enzymatic mechanisms which are responsible for the hydrolysis of conjugated 3-HANA (Watanabe and Minegishi, 1972;Watanabe et al, 19723).…”

A new aspect of the urinary excretion of tryptophan metabolites in patients with cancer of the bladder

“…In previous papers (Teulings et al, 1973(Teulings et al, , 1975 we have demonstrated that the basal urinary concentration of free 3-hydroxyanthranilic acid, which as a mean was found to be high in patients with untreated bladder cancer, is significantly lower in patients treated for the disease. The importance of this observation is that the presence of tumor in the urinary tract might be.…”

“…It was hypothesized that metabolites of tryptophan, increasingly generated by faulty metabolism, may be the etiological agents in non-industrial bladder cancer. That an abnormal metabolism of tryptophan occurs in certain patients with bladder cancer was concluded from studies in which the functional capacity of the pathway was tested by loading the patients with tryptophan (Brown et al, 1960).In previous papers (Teulings et al, 1973(Teulings et al, , 1975 we have demonstrated that the basal urinary concentration of free 3-hydroxyanthranilic acid, which as a mean was found to be high in patients with untreated bladder cancer, is significantly lower in patients treated for the disease. The importance of this observation is that the presence of tumor in the urinary tract might be.…”

Efeitos da luz sobre o metabolismo de triptofano em melanócitos e melanomas

“…Além disso, HK pode suprimir a proliferação de linfócitos T-CD4 + e induzir o desenvolvimento do fenótipo regulatório (Zaher et al, 2011). AA e HAA estão envolvidos com a etiologia do câncer de bexiga (Teulings et al, 1973) e ambos metabólitos podem auto-oxidar e gerar radicais intermediários mutagênicos que podem interagir com o mesmo receptor da KYN, o AhR (Chung et al, 2011). Além disso, o aumento de HAA induz apoptose em linfócitos T CD8 + , e a proliferação de todos os tipos de linfócitos é bloqueada (Weber et al, 2006).…”

“…A enzima KYNU, responsável pela conversão de KYN em AA e HAA teve um aumento significativo de 30 vezes após 48 horas de radiação com a dose de 3 J/cm² em melanomas. Esses dois metabólitos já foram descritos e relacionados a outros tipos de tumores, como no câncer de bexiga (Teulings et al, 1973) et al, 2009).…”