Ni Dan, Ho Dah H, Vijjeswarapu Mary, Felix Edward, Rhea P Robyn, Newman Robert A
Department of Experimental Therapeutics, Unit 601, University of Texas M.D. Anderson Cancer Center, 8000 El Rio, Houston, TX 77054, USA.
J Exp Ther Oncol. 2003 Jan-Feb;3(1):47-52. doi: 10.1046/j.1359-4117.2003.01066.x.
Homoharringtonine (HHT), first isolated from the Chinese evergreen Cephalotaxus harringtonia, has been demonstrated to have a broad antitumor activity in rodents and antileukemic effects in humans. We found that HHT was metabolized to an acid product [HHT-acid; 2'-hydroxy-2'-(alpha-acetic acid)-6'-hydroxy-6'-methylheptanoyl cephalotaxine] when incubated with either human plasma or mouse plasma in vitro. The conversion was faster, however, in mouse plasma, and was both time- and temperature-dependent. Boiled plasma prevented the conversion of HHT to HHT-acid, suggesting that the conversion was enzymatically mediated. When mice were given an intravenous (i.v.) injection of HHT (4 mg/kg), the HHT-acid metabolite was found in both plasma and urine. In mice, HHT-acid was detected in the plasma within 5 min of the i.v. injection of HHT and declined rapidly thereafter. The initial half-lives (t 1/2 alpha) of HHT and HHT-acid were 9 and 17 min, respectively. Twenty-four hours after HHT dosing in mice, approximately 29% of the dose was excreted in the urine as HHT and 20% as HHT-acid. High-pressure liquid chromatography and mass spectrometry were used to confirm the identity and quantify HHT and its metabolite, HHT-acid. The HHT concentration inhibiting 50% of the growth of human leukemic HL-60 cells was 20 ng/ml, while for HHT-acid it was 14,500 ng/ml, indicating that the acid form was more than 700 times less cytotoxic than HHT. The lethal dose of HHT affecting 50% (LD50) of mice was 6.7 mg/kg, but HHT-acid produced no apparent toxic effects at doses up to 280 mg/kg.
高三尖杉酯碱（HHT）最初是从中国的粗榧中分离出来的，已被证明在啮齿动物中具有广泛的抗肿瘤活性，在人类中具有抗白血病作用。我们发现，当HHT在体外与人血浆或小鼠血浆一起孵育时，它会代谢为一种酸性产物[HHT-酸；2'-羟基-2'-(α-乙酸)-6'-羟基-6'-甲基庚酰粗榧碱]。然而，在小鼠血浆中这种转化更快，并且是时间和温度依赖性的。煮沸的血浆可阻止HHT转化为HHT-酸，这表明该转化是由酶介导的。当给小鼠静脉注射（i.v.）HHT（4mg/kg）时，在血浆和尿液中均发现了HHT-酸代谢物。在小鼠中，静脉注射HHT后5分钟内血浆中就检测到了HHT-酸，此后迅速下降。HHT和HHT-酸的初始半衰期（t1/2α）分别为9分钟和17分钟。给小鼠注射HHT 24小时后，约29%的剂量以HHT形式经尿液排出，20%以HHT-酸形式排出。采用高压液相色谱和质谱法来确认HHT及其代谢物HHT-酸的身份并进行定量。抑制人白血病HL-60细胞生长50%的HHT浓度为20ng/ml，而HHT-酸的浓度为14500ng/ml，这表明酸性形式的细胞毒性比HHT低700多倍。影响50%（LD50）小鼠的HHT致死剂量为6.7mg/kg，但HHT-酸在高达280mg/kg的剂量下未产生明显的毒性作用。
