Overexpression of arginase alters circulating and tissue amino acids and guanidino compounds and affects neuromotor behavior in mice

Arginine is an intermediate of the ornithine cycle and serves as a precurso r for the synthesis of nitric oxide, creatine, agmatine and proteins. It is considered to be a conditionally essential amino acid because endogenous s ynthesis only barely meets daily requirements. In rapidly growing suckling neonates, endogenous arginine biosynthesis is crucial to compensate for the insufficient supply of arginine via the milk. Evidence is accumulating tha t the intestine rather than the kidney plays a major role in arginine synth esis in this period. Accordingly, ectopic expression of hepatic arginase in murine enterocytes by genetic modification induces a selective arginine de ficiency. The ensuing phenotype, whose severity correlates with the level o f transgene expression in the enterocytes, could be reversed with arginine supplementation. We analyzed the effect of arginine deficiency on guanidine metabolism and neuromotor behavior. Arginine-deficient transgenic mice con tinued to suffer from an arginine deficiency after the arginine biosyntheti c enzymes had disappeared from the enterocytes. Postweaning catch-up growth in arginine-deficient mice was characterized by increased levels of all me asured amino acids except arginine. Furthermore, plasma total amino acid co ncentration, including arginine, was significantly lower in adult male than in adult female transgenic mice. Decreases in the concentration of plasma and tissue arginine led to significant decreases in most metabolites of arg inine. However, the accumulation of the toxic guanidino compounds, guanidin osuccinic acid and methylguanidine, corresponded inversely with circulating arginine concentration, possibly reflecting a higher oxidative stress unde r hypoargininemic conditions. In addition, hypoargininemia was associated w ith disturbed neuromotor behavior, although brain levels of toxic guanidino compounds and ammonia were normal.