Pathological apoptosis by xanthurenic acid, a tryptophan metabolite: activation of cell caspases but not cytoskeleton breakdown.

BACKGROUND: A family of aspartate-specific cysteinyl proteases, named caspases, mediates programmed cell death, apoptosis. In this function, caspases are important for physiological processes such as development and maintenance of organ homeostasis. Caspases are, however, also engaged in aging and disease development. The factors inducing age-related caspase activation are not known. Xanthurenic acid, a product of tryptophan degradation, is present in blood and urine, and accumulates in organs with aging. RESULTS: Here, we report triggering of apoptotic key events by xanthurenic acid in vascular smooth muscle and retinal pigment epithelium cells. Upon exposure of these cells to xanthurenic acid a degradation of ICAD/DFF45, poly(ADP-ribose) polymerase, and gelsolin was observed, giving a pattern of protein cleavage characteristic for caspase-3 activity. Active caspase-3, -8 and caspase-9 were detected by Western blot analysis and immunofluorescence. In the presence of xanthurenic acid the amino-terminal fragment of gelsolin bound to the cytoskeleton, but did not lead to the usually observed cytoskeleton breakdown. Xanthurenic acid also caused mitochondrial migration, cytochrome C release, and destruction of mitochondria and nuclei. CONCLUSIONS: These results indicate that xanthurenic acid is a previously not recognized endogenous cell death factor. Its accumulation in cells may lead to accelerated caspase activation related to aging and disease development.

[Toxicity and tolerance of tryptophan and its metabolites]. / Sulla tossicità e tollerabilità del triptofano e di suoi metaboliti.

For the therapeutic use of tryptophan it is necessary to know its toxicity and pharmacological effects; but very few data are reported in literature on these aspects. On the other hand there are many researches on tryptophan metabolism after a load test and related side effects. From these data it appears that a tryptophan dose of 100 mg/Kg body weight per os is usually well tolerated with exception of some short and slight gastric troubles (vomit, etc.). The lack of references to repeated and long lasting administrations (chronic toxicity) and of a therapeutic index must be filled. Side effects due to a single dose of 5.OH-tryptophan, e.g. head twitches, resemble those due to serotonine. With regard to the most important metabolites of the kynurenine pathway, the available data have been obtained with kynurenine and especially with xanthurenic acid. These compounds have a low toxicity and do not appear to have important pharmacological properties. However, systematic researches are necessary before using these compounds either in load tests or for therapy in man.