Research Notes: Uridine

From Treatment of Mitochondrial Cytopathies (Medscape Pediatrics)

Uridine will soon be under investigation as a treatment for mitochondrial disorders. Uridine is a pyrimidine nucleotide, required for synthesis of RNA and DNA. Normal cell and organ function rely on adequate synthesis, transport, and interconversions of pyrimidines. The synthetic pathway for uridine synthesis involves the mitochondrial dehydrogenation of dihydrooroate to oroate, which is intimately linked with CoQ10 recycling and normal electron transport chain function. Any process that interferes with CoQ10 recycling or electron transport chain function can impair oroate formation. The process of uridine synthesis concludes with condensing orotic acid with phosphoribosyl pyrophosphate (PRPP) to form uridine monophosphate. Disordered oxidative phosphorylation will impede the de novo synthesis of pyrimidines and further exacerbate cellular dysfunction. The theoretical argument for treating with exogenous uridine is to overcome the relative deficit due to impaired synthesis leading to improved cellular health.

Hereditary orotic aciduria produces a primary uridine deficiency and results in a syndrome of failure to thrive, megaloblastic anemia, orotic aciduria, congenital malformations, transient immunoglobulin deficiency, immune deficiency, and developmental delays. Lifelong supplemental uridine is required and may reverse some of the manifestations of this deficient state. Postulated beneficial effects of uridine are based primarily on animal research and include: appetite stimulation, anticonvulsant effects, prevention of lactic acid overproduction, antidepressant, cardioprotective, and prevention of cerebral edema, among others. Human trials are planned. Side effects have been reported and more commonly include a transient increase in seizure activity upon initiation of therapy, nausea, vomiting, and/or diarrhea (Robert Naviaux, personal communication, 2001).