Pastorelli R, Ancidei A, Fanelli R, Airoldi L
Laboratory of Environmental Pharmacology and Toxicology, Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.
Food Chem Toxicol. 1988 May;26(5):419-23. doi: 10.1016/0278-6915(88)90052-x.
The urinary metabolic pattern of N-nitrosobutyl(4-hydroxybutyl)amine (NB4HBA) administered ip at a dose of 5 mg/kg body weight was studied in animals either pretreated with butylated hydroxyanisole (BHA) as a single oral dose of 50 or 250 mg/kg, or fed a diet containing 0.1 or 0.5% BHA. The 24-hr urinary excretion of NB4HBA, its glucuronic acid-conjugate (NB4HBA-G) and N-nitrosobutyl(3-carboxypropyl)amine (NB3CPA) in control rats were 0.12, 0.75 and 30% of the administered dose, respectively, and were not changed after a single oral dose of 50 mg BHA/kg. NB4HBA-G was significantly reduced in the urine of rats given 250 mg BHA/kg. In vitro assays carried out using rat-hepatic microsomal preparations as the source of the enzyme UDP-glucuronyl transferases (GT) and NB4HBA as the substrate, suggest that a competition between NB4HBA and BHA for the same enzyme may be the cause of the decreased NB4HBA-G excretion observed in vivo. A fourfold increase in NB4HBA-G urinary excretion was observed after chronic 0.5% BHA feeding; moreover, the glucuronic acid-conjugate of NB3CPA (NB3CPA-G), which was not detected in the controls or after acute BHA treatment, appeared in the urine of rats given dietary BHA for 3 wk, accounting for about 10% of the administered NB4HBA. In vitro experiments indicate that the increased glucuronides excretion may be the result of an elevated hepatic GT activity.
以5毫克/千克体重的剂量腹腔注射N-亚硝基丁基（4-羟基丁基）胺（NB4HBA）后，在以下动物中研究了其尿液代谢模式：一是预先经口单次给予50或250毫克/千克丁基羟基茴香醚（BHA）的动物，二是喂食含0.1%或0.5%BHA饮食的动物。对照大鼠中NB4HBA、其葡萄糖醛酸结合物（NB4HBA-G）和N-亚硝基丁基（3-羧丙基）胺（NB3CPA）的24小时尿排泄量分别为给药剂量的0.12%、0.75%和30%，经口单次给予50毫克BHA/千克后无变化。给予250毫克BHA/千克的大鼠尿液中NB4HBA-G显著减少。以大鼠肝微粒体制剂作为尿苷二磷酸葡萄糖醛酸基转移酶（GT）的酶源、NB4HBA作为底物进行的体外试验表明，NB4HBA和BHA对同一酶的竞争可能是体内观察到的NB4HBA-G排泄减少的原因。慢性喂食0.5%BHA后，NB4HBA-G的尿排泄量增加了四倍；此外，在对照或急性BHA处理后未检测到的NB3CPA的葡萄糖醛酸结合物（NB3CPA-G）出现在喂食BHA饮食3周的大鼠尿液中，约占给药NB4HBA的10%。体外实验表明，葡萄糖醛酸结合物排泄增加可能是肝脏GT活性升高的结果。
