Tracy J W, Catto B A, Webster L T
Department of Comparative Biosciences, University of Wisconsin-Madison 53706-1102.
Drug Metab Dispos. 1991 Mar-Apr;19(2):508-15.
N-(5-nitro-2-thiazolyl)-N'-carboxymethylurea (NTCU) has been identified as a urinary metabolite of the antischistosomal drug niridazole [1-(5-nitro-2-thiazolyl)-2-imidazolidinone]. When DBA/2J mice were treated with [14C]niridazole, a metabolite comprising 12-14% of the total radioactivity in 24-hr urine samples was resolved by HPLC. The compound was subsequently isolated from pooled urine of niridazole-treated patients. It was identified as NTCU by mass spectrometry, and the deduced structure was confirmed by chemical synthesis. NTCU is unique among known niridazole metabolites, because it lacks an intact imidazolidinone ring. Its structure allows for a ketoenol tautomerism in which the enolate is stabilized by conjugation with the nitrothiazole ring, as evidenced by a pH-dependent 80-nm red shift in the absorption spectrum. We hypothesized that NTCU arises via oxidation of an acyclic aldehyde tautomer of 5-hydroxyniridazole, one of two proximate oxidative niridazole metabolites. Indirect evidence for the aldehyde tautomer included the fact that 5-hydroxyniridazole displayed the same pH-dependent spectral shift as NTCU with a single isobestic point at 388 nm. The proposed precursor-product relationship was confirmed when we found that NTCU formation from 5-hydroxyniridazole was catalyzed by NAD(+)-dependent aldehyde dehydrogenase (EC 1.2.1.3). The activity copurified with benzaldehyde dehydrogenase activity from mouse liver cytosol. Furthermore, benzaldehyde was a competitive inhibitor of 5-hydroxyniridazole dehydrogenase activity. These results demonstrate that 5hydroxyniridazole is not an end product of niridazole metabolism. Because biotransformation of niridazole to its 4- and 5-hydroxy derivatives has been implicated in the drug's carcinogenicity and central nervous system toxicity, NTCU formation appears to represent a detoxication pathway in mammals.
N-(5-硝基-2-噻唑基)-N'-羧甲基脲（NTCU）已被确定为抗血吸虫药物硝唑咪[1-(5-硝基-2-噻唑基)-2-咪唑烷酮]的一种尿液代谢产物。当用[14C]硝唑咪处理DBA/2J小鼠时，通过高效液相色谱法分离出一种代谢产物，其在24小时尿液样本中的放射性占总放射性的12% - 14%。随后从硝唑咪治疗患者的合并尿液中分离出该化合物。通过质谱鉴定其为NTCU，并通过化学合成证实了推导的结构。NTCU在已知的硝唑咪代谢产物中是独特的，因为它缺乏完整的咪唑烷酮环。其结构允许酮 - 烯醇互变异构，其中烯醇盐通过与硝基噻唑环共轭而稳定，这在吸收光谱中pH依赖的80纳米红移中得到证明。我们推测NTCU是通过5-羟基硝唑咪的无环醛互变异构体氧化产生的，5-羟基硝唑咪是硝唑咪两种直接氧化代谢产物之一。醛互变异构体的间接证据包括5-羟基硝唑咪与NTCU表现出相同的pH依赖光谱位移，在388纳米处有一个单一的等吸收点。当我们发现5-羟基硝唑咪形成NTCU是由NAD(+)依赖性醛脱氢酶（EC 1.2.1.3）催化时，所提出的前体 - 产物关系得到了证实。该活性与小鼠肝细胞溶质中的苯甲醛脱氢酶活性共纯化。此外，苯甲醛是5-羟基硝唑咪脱氢酶活性的竞争性抑制剂。这些结果表明5-羟基硝唑咪不是硝唑咪代谢的终产物。由于硝唑咪向其4-和5-羟基衍生物的生物转化与该药物的致癌性和中枢神经系统毒性有关，NTCU的形成似乎代表了哺乳动物中的一种解毒途径。
