Abstract: A rat neuroma cell line (B103 4C), deficient of hypoxanthine‐guanine phosphoribosyltransferase (HGPRT), was utilized as a model tissue in search for the biochemical basis of the Lesch‐Nyhan syndrome (LNS). The HGPRT‐deficient neurons exhibited the following properties: an almost complete absence of uptake of guanine and of hypoxanthine into intact cell nucleotides (0.92% and 0.69% of normal, respectively); a significant increase in the availability of 5′‐phosphoribosyl‐1‐pyrophosphate; a three‐ to fourfold acceleration of the rate of de novo nucleotide synthesis; a normal excretion of xanthine, but 15‐fold increase in the excretion of hypoxanthine into the culture media; a normal cellular purine nucleotide content, including the absence of 5‐amino‐4‐imidazole carboxamide nucleotides (Z‐nucleotides), but enhanced turnover of adenine nucleotides (loss of 86% of the radioactivity of the prelabeled pool in 24 h, in comparison to 73% in the normal line), and an elevated UTP content. The results suggest that, under physiological conditions, guanine salvage does not occur in the normal neurons, but that hypoxanthine salvage is of great importance in the homeostasis of the adenine nucleotide pool. The finding of the normal profile of purine nucleotides in the HGPRT‐deficient neurons indicates that the lack of hypoxanthine salvage is adequately compensated by the enhanced de novo nucleotide synthesis. These results did not furnish evidence in support of the possibility that GTP or ATP depletion, or Z‐nucleotide accumulation, occurs in HGPRT‐deficient neurons and that these are etiological factors causing the neurological abnormalities in LNS. On the other hand, the results point to the possibility that elevated hypoxanthine concentration in the brain may have an etiological role in the pathogenesis of LNS.
|Number of pages||7|
|Journal||Journal of Neurochemistry|
|State||Published - Aug 1993|
- Adenine nucleotides
- Hypoxanthine‐guanine phosphoribosyltransferase (HGPRT) deficiency
- Lesch‐Nyhan syndrome
- Neuroma cell line