Effect of 3-hydroxyanthranilic acid on the mitochondrial respiratory system.

Studies on the metabolites of tryptophan in urine, in various neoplastic diseases, have shown an unusual excretion pattern, some of these compounds being eliminated in greater amounts than in normal human beings (Boyland & Williams, 1956a, b; Musajo, Benassi & Parpajola, 1955; Quagliariello, Tancredi, Fedele & Saccone, 1961; Tompsett, 1959; Ivanova & Ramonova-Tskhovrebova, 1960; Price & Brown, 1962). Particularly in bladder cancer there appeared to be an excretion of considerable quantities of 3-hydroxyanthranilic acid and 3-hydroxykynurenine. The significance of the accumulation in the body of these biological o-aminophenols in relation to neoplastic disease is still not clear. However, a number of o-aminophenols are known to induce bladder cancer (Boyland, 1958), and it has been shown that 3hydroxyanthranilic acid and 3-hydroxykynurenine can induce experimental cancer of the bladder (Allen, Boyland, Dukes, Horning & Watson, 1957), and 3-hydroxyanthranilic acid some forms of leukaemia (Ehrhart & Georgii, 1959). Further, Dunning, Curtis & Mann (1950) reported that bladder cancer caused by 2-acetamidofluorene arises in practically all cases in rats when the diet is supplemented with tryptophan. We decided to investigate the effects of these tryptophan metabolites on the main cellular processes, and first studied the effect of 3-hydroxyanthranilic acid on mitochondrial oxidative phosphorylation. It is generally known that substituted phenols (thyroxine, dinitrophenols etc.) act on mitochondrial processes. Quagliariello, Saccone, Rinaldi & Alioto (1959) have shown an antagonism between 3-hydroxyanthranilic acid and vitamin K. The structural configuration of 3-hydroxyanthranilic acid is such that it may account for its antagonism towards biological naphthaquinones and benzoquinones (see also Mentzer, 1948), which may play a part in the oxidative phosphorylation. 3-Hydroxyanthranilic acid apparently uncoupled oxidative phosphorylation and inhibited the oxidation of oc-oxoglutarate by rat-liver and ratheart mitochondria (Quagliariello, Papa & Saccone, 1962 a, b). It also activated glycolysis in a fraction of rat liver (Papa, Budillon & Quagliariello, 1962b) and increased the incorporation of labelled amino acids into the proteins of rat-liver preparations (Barnabei, Papa & Quagliariello, 1963). The present paper is concerned with a detailed study of the effect of 3-hydroxyanthranilic acid on the oxidation of o-oxoglutarate and on other NAD-dependent mitochondrial oxidations. The effect of 3-hydroxyanthranilic acid on adenosine triphosphatase and on the structural state of mitochondria is also described.