White I N, Cahill A, Davies A, Carthew P
MRC Toxicology Unit, Carshalton, Surrey, UK.
Arch Toxicol. 1992;66(2):100-6. doi: 10.1007/BF02342502.
Pathological lesions to male Fischer rats were investigated 24 h after the administration of 3-amino-1,2,4-benzotriazine-1,4- dioxide (SR 4233) or nitromin, two compounds which need to undergo bioreductive activation in order to exert their toxic effects. Although SR 4233 reduction leads to a putative free radical species while with nitromin a bifunctional alkylating agent is formed, in both instances, the bone marrow was a major target organ. However, the response of other organs to these compounds differed. SR 4233 caused lesions to the olfactory epithelium, liver, kidney and thymus. Nitromin caused focal haemorrhages on the intestine, which were reduced in germ-free rats. Rates of reduction of SR 4233 or nitromin were determined under anaerobic conditions using microsomal preparations from target tissues. With SR 4233 as a substrate, reductase activities were highest in the olfactory epithelium, 6 fold higher than in the liver. SR 4233 reductase activities generally correlated with those of NADPH:cytochrome c reductase or the concentration of cytochrome P-450 reductase protein in the affected organs while with nitromin, there appeared to be no such relationship. The present results support the concept that the expression of pathological damage in vivo is a multifactorial process and does not directly correlate with initial rates of reduction of either drug determined in vitro.
在给予3-氨基-1,2,4-苯并三嗪-1,4-二氧化物（SR 4233）或硝米芬24小时后，对雄性Fischer大鼠的病理损伤进行了研究。这两种化合物需要经过生物还原激活才能发挥其毒性作用。虽然SR 4233的还原会产生一种假定的自由基，而硝米芬会形成一种双功能烷基化剂，但在这两种情况下，骨髓都是主要的靶器官。然而，其他器官对这些化合物的反应有所不同。SR 4233导致嗅觉上皮、肝脏、肾脏和胸腺出现病变。硝米芬导致肠道出现局灶性出血，在无菌大鼠中这种出血有所减少。在厌氧条件下，使用来自靶组织的微粒体制剂测定SR 4233或硝米芬的还原速率。以SR 4233作为底物时，还原酶活性在嗅觉上皮中最高，比肝脏中的高6倍。SR 4233还原酶活性通常与受影响器官中NADPH：细胞色素c还原酶的活性或细胞色素P-450还原酶蛋白的浓度相关，而对于硝米芬，似乎不存在这种关系。目前的结果支持这样一种观点，即体内病理损伤的表达是一个多因素过程，与体外测定的任何一种药物的初始还原速率没有直接关联。
