Stavric B, Nera E A
Clin Toxicol. 1978;13(1):47-74. doi: 10.3109/15563657808988228.
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.
一段时间以来，一直需要一种可获取、可重复且成本低廉的动物模型来进行高尿酸血症的毒理学评估。许多作者试图通过向各种动物物种（狗、兔子、大鼠）施用高剂量尿酸来开发这样的模型，但这些物种中强大的肝脏尿酸酶阻碍了持续性高尿酸血症的发展。约翰逊等人[4]、斯塔夫里克等人[5]以及其他一些研究人员[72, 75]成功地使用氧嗪酸钾[63]来阻断肝脏尿酸酶的作用，并在大鼠[4, 5, 68, 69, 72, 74, 76, 80]、兔子[66]、杂种狗[67]、小鼠[65]和猪[64]中诱导出高尿酸血症。经氧嗪酸盐处理的大鼠不仅可以作为研究尿酸肾病的有用动物模型，还可以用于许多其他与尿酸相关的毒理学评估。该模型已被用于评估影响尿酸排泄的药物，确定哪些饮食因素会影响血清尿酸盐，或评估某些与尿酸相关疾病的可能治疗药物。行为科学家也可以使用相同的模型，近年来，尿酸研究在行为科学家当中越来越受欢迎[33, 137]。用于诱导高尿酸血症的理想尿酸酶抑制剂应该是不可逆、非竞争性且相对无毒的，这样其活性将独立于高浓度的尿酸，并且在低剂量水平就能实现有效抑制。氧嗪酸不是理想的尿酸酶抑制剂，因为它具有竞争性且相对较快地从体内消除。尽管相对无毒，但氧嗪酸及其盐类是可能干扰其他一些代谢系统的外来物质。有可能通过对氧嗪酸分子进行适当取代或引入不同类型的化合物（如重氮次黄嘌呤、巴比妥类药物或类似物质的衍生物）来开发出理想的，或至少是更好的抑制剂。在对尿酸酶抑制大鼠模型进行此类改进之前，易于获得的氧嗪酸钾可以用作体内尿酸酶的有效抑制剂。
