Longo V, Citti L, Gervasi P G
Istituto di Mutagenesi e Differenziamento del CNR, Pisa, Italy.
Toxicol Lett. 1988 Dec;44(3):289-97. doi: 10.1016/0378-4274(88)90168-3.
The metabolism of hexamethylphosphoramide (HMPA), aminopyrine, ethoxycoumarin, ethoxyresorufin, and pentoxyresorufin, by the monooxygenase cytochrome P-450-dependent system, was studied in microsomes from nasal epithelial membranes and liver tissue of Sprague-Dawley rats. Nasal metabolism rates for the different substrates ranged from 9% of liver values for aminopyrine to 83% for ethoxycoumarin. HMPA-demethylase activity followed Michaelis-Menten kinetics in nasal mucosa microsomes but was biphasic in those from liver. SKF 525A, metyrapone, dioxolane and alpha-naphthoflavone (ANF), inhibitors of various P-450 monoxygenases, were examined with regard to inhibition of nasal and liver ethoxycoumarin deethylase. In addition, activity of epoxide hydrolase, glutathione S-transferase, DT-diaphorase and UDP-glucuronyltransferase (UDP-GT) in nasal tissue homogenates were investigated. These activities were generally lower than those present in the liver. Various attempts to increase the activity of oxidative enzymes in nasal tissue by PB, 3-MC and ethanol failed, 3-MC and PB doubled the microsomal UDP-GT and the epoxide hydrolase activities. The results together with data from the literature suggest that the balance between P-450 isozymes and detoxifying enzymes differs in the nose compared with the liver. The activities of these enzymes in nasal tissue of different strains of rats also varies substantially with implications regarding the metabolic fate and activation of inhaled xenobiotics.
利用依赖细胞色素P - 450的单加氧酶系统，对六甲基磷酰胺（HMPA）、氨基比林、乙氧香豆素、乙氧试卤灵和戊氧试卤灵在斯普拉格 - 道利大鼠鼻黏膜上皮和肝组织微粒体中的代谢进行了研究。不同底物的鼻代谢率范围为：氨基比林为肝代谢率的9%，乙氧香豆素为83%。HMPA - 脱甲基酶活性在鼻黏膜微粒体中遵循米氏动力学，但在肝微粒体中呈双相性。研究了各种P - 450单加氧酶抑制剂SKF 525A、美替拉酮、二氧戊环和α - 萘黄酮（ANF）对鼻和肝乙氧香豆素脱乙基酶的抑制作用。此外，还研究了鼻组织匀浆中环氧水解酶、谷胱甘肽S - 转移酶、DT - 黄递酶和尿苷二磷酸葡萄糖醛酸转移酶（UDP - GT）的活性。这些活性通常低于肝脏中的活性。通过苯巴比妥（PB）、3 - 甲基胆蒽（3 - MC）和乙醇增加鼻组织中氧化酶活性的各种尝试均失败，3 - MC和PB使微粒体UDP - GT和环氧水解酶活性增加了一倍。这些结果以及文献数据表明，与肝脏相比，鼻子中P - 450同工酶和解毒酶之间的平衡有所不同。不同品系大鼠鼻组织中这些酶的活性也有很大差异，这对吸入的外源化合物的代谢命运和活化具有重要意义。
