Dambrova M, Uhlén S, Wikberg J E
Department of Pharmaceutical Biosciences, Uppsala University, Sweden.
Pharmacol Toxicol. 1998 Oct;83(4):158-63. doi: 10.1111/j.1600-0773.1998.tb01462.x.
Guanoxabenz (1-(2,6-dichlorobenzylidene-amino)-3-hydroxyguanidine) and guanabenz (1-(2,6-dichlorobenzylidene-amino)-3-guanidine) are both known as centrally active antihypertensive drugs. We have previously shown that enzymatic activity in the rat spleen can induce N-reduction of guanoxabenz, leading to high affinity alpha 2-adrenoceptor binding, due to the formation of the alpha 2-adrenoceptor active drug, guanabenz. The spleen activity appears to reside in xanthine oxidase as it is activated by xanthine and blocked by allopurinol. We report that high affinity guanoxabenz binding is also induced in rat brain membranes after addition of NADH or NADPH cofactors. However, the brain process was clearly different from that of the spleen, as the formation of high affinity binding in the brain was not blocked by allopurinol. Moreover the NADH/NADPH activated mechanism of the brain membranes was not blocked by carbon monoxide and SKF525A, thus the activity appears not to reside in cytochrome P450 enzymes. Instead the activity was blocked by menadione and dicumarol. We conclude that the rat cerebral cortex contains an enzymatic activity that may activate guanoxabenz leading to formation of a metabolite showing high affinity for alpha 2-adrenoceptors. We also conclude that the rat brain activity is clearly distinct from that of the rat spleen.
胍那苄（1-(2,6-二氯亚苄基氨基)-3-羟基胍）和胍法辛（1-(2,6-二氯亚苄基氨基)-3-胍）均为已知的中枢性抗高血压药物。我们之前已表明，大鼠脾脏中的酶活性可诱导胍那苄的N-还原，由于α2-肾上腺素能受体活性药物胍法辛的形成，从而导致与α2-肾上腺素能受体的高亲和力结合。脾脏活性似乎存在于黄嘌呤氧化酶中，因为它可被黄嘌呤激活并被别嘌呤醇阻断。我们报告称，在添加NADH或NADPH辅因子后，大鼠脑膜中也会诱导出胍那苄的高亲和力结合。然而，脑内过程与脾脏明显不同，因为脑内高亲和力结合的形成不受别嘌呤醇的阻断。此外，脑膜的NADH/NADPH激活机制不受一氧化碳和SKF525A的阻断，因此该活性似乎不存在于细胞色素P450酶中。相反，该活性被甲萘醌和双香豆素阻断。我们得出结论，大鼠大脑皮层含有一种酶活性，该活性可能激活胍那苄，导致形成一种对α2-肾上腺素能受体具有高亲和力的代谢产物。我们还得出结论，大鼠脑内活性与大鼠脾脏活性明显不同。
