Use of the uricase-inhibited rat as an animal model in toxicology

Abstract

An accessible, reproducible, and inexpensive animal model for toxicologic evaluation of hyperuricemic conditions has been required for some time. A number of authors have tried to develop such a model by administering high doses of uric acid to various animal species (dog, rabbit, rat) but the potent liver uricase in these species prevented development of sustained hyperuricemia. Johnson et al. [4], Stavric et al. [5], and a number of other investigators [72, 75] successfully used potassium oxonate [63] to block the effect of hepatic uricase and to produce hyperuricemia in rats [4, 5, 68, 69, 72, 74, 76, 80], rabbits [66], mongrel dogs [67], mice [65], and pigs [64]. The oxonate-treated rat can serve as a useful animal model not only in investigation of the uric acid nephropathy, but also in a number of other toxicologic evaluations connected with uric acid. This model has been used to evaluate drugs that affect uric acid excretion, to determine which dietary factors affect serum urates, or to evaluate possible therapeutic agents in certain disorders associated with uric acid. The same model could also be used by behavioral scientists, for whom research on uric acid has become increasingly popular in recent years [33, 137]. The ideal uricase inhibitor for induction of hyperuricemia would be one which is irreversible, noncompetitive, and relatively nontoxic, so that its activity would be independent of high levels of uric acid, and effective inhibition could be attained at low dosage levels. Oxonic acid is not an ideal uricase inhibitor, because it is competitive and is eliminated from the body relatively rapidly. Although relatively nontoxic, oxonic acid and its salts are foreign substances that could interfere with some other metabolic systems. The possibility exists that an ideal, or at least a better inhibitor, could be developed by appropriate substitutions on the molecule of oxonic acid or by introducing different types of compounds such as derivatives of diazohypoxanthines, barbiturates, or similar substances. Until such improvements on the uricase-inhibited rat models are available, potassium oxonate, which is easily obtainable, can be used as an effective inhibitor of uricase in vivo.