Nucleotide pool imbalances in the livers of patients with urea cycle disorders associated with increased levels of orotic aciduria.

Liver samples obtained at autopsy from patients with ornithine transcarbamylase (OTC) deficiency, a urea cycle disorder that is associated with high levels of orotic acid biosynthesis and excretion were analysed for nucleotide pools. As a control, liver samples from patients with a deficiency of mitochondrial carbamyl phosphate synthetase (CPS-I) which is not associated with increased levels of orotic acidurias were also analysed. The results show that liver tissue from OTC deficiency patients exhibited an increased ratio of uridine nucleotides to adenosine nucleotides, while in CPS-I deficiency patients, no such increase was noted. This study indicates that genetic disorders that are associated with increased loads of orotic acid exhibit abnormally high ratios of uridine to adenosine nucleotides in the liver. This type of imbalance is analogous to that seen in the liver of rats and mice exposed to an orotic acid supplemented or an arginine-deficient diet under liver tumor promoting conditions. It is likely that an imbalance in nucleotide pools may have a significant role in the pathophysiology associated with these disorders.