Studies on Carnitine Metabolism of Various Disorders Accompanied by Hyperammonemia

Recently, the carnitine status of various disorders accompanied by hyperammonemia has been studied, and carnitine deficiency syndromes, secondary to a variety of genetic disorders, have been found. The author measured the serum and tissue carnitine levels of various disorders accompanied by hyperammonemia. In patients with ornithine transcarbamylase （OTC） and carbamylphosphate synthetase （CPS-I） deficiencies, free carnitine levels in the serum were decreased and acylcarnitine levels were increased. These findings were also observed in liver tissues. However, the serum and hepatic carnitine concentrations of congenital hyperammonemic patients with other cytosolic enzyme deficiencies of the urea cycle were within normal limits. Carnitine levels in the serum and liver tissues of some patients with OTC deficiency decreased gradually with age. In the patient with CPS I deficiency, the mean blood ammonia levels decreased significantly, accompanied by an increase in serum and urine free carnitine levels after oral administration of L-carnitine （lOmg/kg/day）. The serum free carnitine levels of patients receiving sodium valproate （VPA） therapy decreased and their acylcarnitine free carnitine ratios increased. There existed a definite correlation between serum free carnitine and blood ammonia. Primary cultured rat hepatocytes were used to study the effect of VPA on the levels of ammonia and urea synthesis in culture medium. The addition of VPA to the culture medium resulted in an increase of ammonia and a decrease of urea synthesis. The carnitine content of hepatocytes and citrulline synthesis by hepatocytes were also decreased following VPA addition, but OTC and CPS-I activities were unchanged. When L-carnitine was added with VPA to the medium, the levels of ammonia decreased and urea synthesis increased. These observations indicate that VPA-induced hyperammonemia is caused by inhibition of citrulline synthesis followed by hepatic carnitine deficiency, and suggest that L-carnitine may be effective in preventing VPA-induced hyperam- monemia. In future studies, the carnitine status in congenital hyperammonemia and VPA therapy should be investigated, since oral administration of L-carnitine may be effective in patients with secondary carnitine deficiency.departmental bulletin pape