Vitseva Olga, Flockhart David A, Jin Yan, Varghese Sonia, Freedman Jane E
Boston University School of Medicine, 715 Albany St., W507, Boston, MA 02118, USA.
J Pharmacol Exp Ther. 2005 Mar;312(3):1144-50. doi: 10.1124/jpet.104.076315. Epub 2004 Oct 27.
Tamoxifen is effective in the prevention and treatment of breast cancer, but its use is associated with an increased risk of thrombosis. The mechanism for this effect is unknown. Reactive oxygen intermediates enhance platelet-dependent thrombosis, and in oncological studies, tamoxifen has been shown to increase production of reactive oxygen species. Therefore, the effects of tamoxifen and its bioactive metabolites on platelet activity and platelet reactive oxygen species were determined. Platelets were incubated with tamoxifen or the metabolites 4-hydroxy-tamoxifen (4-OH), N-desmethyl tamoxifen, or 4-hydroxy-N-desmethyl tamoxifen (endoxifen). Tamoxifen metabolites have been previously shown to possess enhanced bioactivity, and consistent with this observation, tamoxifen metabolites but not tamoxifen modestly increased platelet aggregation. These effects were similar with platelets isolated from male or female subjects. Platelet nitric oxide release or cGMP levels were not altered by incubation with tamoxifen or any of its metabolites. Incubation with tamoxifen metabolites increased stimulation-dependent platelet superoxide release [8.1 +/- 1.6 arbitrary units (a.u.) for control versus 15.2 +/- 3.5 a.u. for 4-OH; P < 0.01]. Coincubation with a superoxide dismutase mimetic eliminated the tamoxifen metabolite-induced enhancement of platelet aggregation. Corresponding to increased superoxide release, incubation with tamoxifen metabolites enhanced the functional activation of NADPH oxidase as determined by phosphorylation of its subunits p47(phox) and p67(phox). In summary, incubation of platelets with the active metabolites of tamoxifen increases stimulation-dependent superoxide release through a NADPH oxidase-dependent mechanism. This results in modest changes in platelet function and seems to be consistent with previous oncological studies demonstrating tamoxifen-dependent increase in reactive oxygen species generation.
他莫昔芬在乳腺癌的预防和治疗中有效，但它的使用与血栓形成风险增加有关。这种作用的机制尚不清楚。活性氧中间体可增强血小板依赖性血栓形成，并且在肿瘤学研究中，已表明他莫昔芬可增加活性氧的产生。因此，确定了他莫昔芬及其生物活性代谢物对血小板活性和血小板活性氧的影响。将血小板与他莫昔芬或代谢物4-羟基他莫昔芬（4-OH）、N-去甲基他莫昔芬或4-羟基-N-去甲基他莫昔芬（内昔芬）一起孵育。他莫昔芬代谢物先前已显示具有增强的生物活性，与此观察结果一致，他莫昔芬代谢物而非他莫昔芬适度增加了血小板聚集。这些作用在从男性或女性受试者分离的血小板中相似。与他莫昔芬或其任何代谢物孵育不会改变血小板一氧化氮释放或cGMP水平。与他莫昔芬代谢物孵育会增加刺激依赖性血小板超氧化物释放[对照组为8.1±1.6任意单位（a.u.），4-OH组为15.2±3.5 a.u.；P<0.01]。与超氧化物歧化酶模拟物共同孵育可消除他莫昔芬代谢物诱导的血小板聚集增强。与超氧化物释放增加相对应，与他莫昔芬代谢物孵育可增强NADPH氧化酶的功能激活，这通过其亚基p47（phox）和p67（phox）的磷酸化来确定。总之，血小板与他莫昔芬的活性代谢物孵育可通过NADPH氧化酶依赖性机制增加刺激依赖性超氧化物释放。这导致血小板功能发生适度变化，似乎与先前的肿瘤学研究一致，这些研究表明他莫昔芬依赖性活性氧生成增加。
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