Deficiency of 5-hydroxyisourate hydrolase causes hepatomegaly and hepatocellular carcinoma in mice

Abstract

With the notable exception of humans, uric acid is degraded to (S)-allantoin in a biochemical pathway catalyzed by urate oxidase, 5-hydroxyisourate (HIU) hydrolase, and 2-oxo-4-hydroxy-4-carboxy-5-ureidoimidazoline decarboxylase in most vertebrate species. A point mutation in the gene encoding mouse HIU hydrolase, Urah, that perturbed uric acid metabolism within the liver was discovered during a mutagenesis screen in mice. The predicted substitution of cysteine for tyrosine in a conserved helical region of the mutantencoded HIU hydrolase resulted in undetectable protein expression. Mice homozygous for this mutation developed elevated platelet counts secondary to excess thrombopoietin production and hepatomegaly. The majority of homozygous mutant mice also developed hepatocellular carcinoma, and tumor development was accelerated by exposure to radiation. The development of hepatomegaly and liver tumors in mice lacking Urah suggests that uric acid metabolites may be toxic and that urate oxidase activity without HIU hydrolase function may affect liver growth and transformation. The absence of HIU hydrolase in humans predicts slowed metabolism of HIU after clinical administration of exogenous urate oxidase in conditions of uric acid-related pathology. The data suggest that prolonged urate oxidase therapy should be combined with careful assessment of toxicity associated with extrahepatic production of uric acid metabolites.N-ethyl-N-nitrosourea mutagenesis | uric acid | 5-hydroxyisourate hydrolase | hepatocellular carcinoma | thrombopoietin U ric acid is the product of purine metabolism. In most mammals, uric acid, or urate, the form that predominates in vivo, is further metabolized to (S)-allantoin (1, 2). In humans and some higher primates, the urate oxidase gene is dysfunctional because of the introduction of premature stop codons during recent evolution (3). A nonfunctional urate oxidase enzyme causes a relative excess of uric acid in humans compared with most other vertebrate species. Because uric acid is relatively insoluble, humans are susceptible to diseases resulting from precipitation of uric acid such as gout and kidney stones as well as urate nephropathy associated with the tumor lysis syndrome. Chronic hyperuricemia in humans has also been linked to the development of cardiovascular disease and hypertension (4, 5).It is unclear why humans have evolved this block in uric acid metabolism during evolution, but suggested theoretical advantages of increased levels of circulating uric acid include its role as a potent antioxidant offering protection from cancer and aging (6) and its potential function in maintenance of adequate blood pressure during periods of low salt intake (7).The components of the full metabolic pathway that converts urate to allantoin in lower mammals have only recently been identified (1). Although it was originally thought that urate oxidase was the sole enzymatic component of this pathway, recent studies have established that conversion of uric acid to allantoin occurs by sequential ch...

Urate as a Physiological Substrate for Myeloperoxidase

“…Even their dismutation to dehydrourate may be harmful because this species hydrolyzes to 5-hydroxyisourate (Scheme 2). This metabolite, which was produced by MPO, has recently been shown to be associated with development of liver tumors in mice (59). Adverse reactions of urate radicals will be kept in check only when ascorbate is available at sufficient concentrations to reduce them back to urate (60,61).…”

Probing the Evolution of Hydroxyisourate Hydrolase into Transthyretin through Active-Site Redesign

“…The first level concerns the evolutionary change of the HIUase peroxisomal targeting signal (PTS) into a signal peptide in TTR. In this respect, it should be pointed out that HIUase in mouse and, presumably, in other vertebrates is confined to hepatocytes, 7 where the urate degradation pathway takes place. Given the same intron/ exon structures of the genes encoding HIUase and TTR, the first coding exon encodes a signal peptide in TTR and a type 2 PTS in HIUase.…”

“…In fact, an inactivating mutation in HIUase leads to hepatomegaly and hepatocellular carcinoma. 7 HIUase is a tetramer formed by the assembly of four identical subunits and characterized by a 222 symmetry. Each monomer is composed of eight antiparallel β-strands, arranged in a topology similar to that of the Greek key β-barrel, and a short α-helix.…”

Uric Acid and Thiocyanate as Competing Substrates of Lactoperoxidase

“…Dehydrourate and 5-hydroxyisourate are electrophilic species that are potentially toxic and are likely to affect host defense as well as the inflammatory response to bacteria. The absence of 5-hydroxyisourate hydrolase in knock-out mice predisposes them to liver cancer (61), which demonstrates that these electrophiles are indeed toxic. In the presence of superoxide, we have shown that LPO catalyzes the production of another electrophile, urate hydroperoxide.…”