Perrine S P, Ginder G D, Faller D V, Dover G H, Ikuta T, Witkowska H E, Cai S P, Vichinsky E P, Olivieri N F
Children's Hospital Oakland Research Institute, Calif 94609.
N Engl J Med. 1993 Jan 14;328(2):81-6. doi: 10.1056/NEJM199301143280202.
Fetal-globin (gamma-globin) chains inhibit the polymerization of hemoglobin S (sickle hemoglobin) and can functionally substitute for the beta-globin chains that are defective or absent in patients with the beta-thalassemias. Identifying safe mechanisms to stimulate fetal-hemoglobin production is therefore of great interest. Previous studies have shown that administering butyrate selectively stimulates the promoter of the human fetal-globin gene and leads to increases in gamma-globin--gene expression in the developing fetus, cultured cells, and animal models.
To determine whether butyrate can stimulate fetal-globin production in humans, we treated three patients (3 to 13 years old) with sickle cell anemia and three patients (7 to 27 years old) with beta-thalassemia syndromes with a short course of intravenous infusions of arginine butyrate. The drug was infused continuously for either two or three weeks; the initial dose was 500 mg per kilogram of body weight per day. Globin-chain ratios, proportions of reticulocytes producing hemoglobin F (F reticulocytes), and levels of gamma-globin messenger RNA (mRNA) were determined before and during treatment.
In all six patients, fetal-globin synthesis increased by 6 to 45 percent above pretreatment levels (P < 0.01). The proportion of F reticulocytes increased about twofold, and the level of gamma-globin mRNA increased twofold to sixfold. The increase in gamma-globin synthesis led to improvement in the globin-chain ratios in the patients with thalassemia. The treatment of one patient was extended for seven weeks, and her hemoglobin level increased from 4.7 to 10.2 g per deciliter (2.9 to 6.3 mmol per liter). Side effects were minimal; one patient had a transient increase in serum aminotransferase concentrations.
In patients with beta-hemoglobinopathies butyrate, a natural fatty acid, can significantly and rapidly increase fetal-globin production to levels that can ameliorate beta-globin disorders. Further trials of this class of compounds are warranted to determine long-term tolerance and efficacy in patients with sickle cell anemia or beta-thalassemia.
胎儿血红蛋白（γ-珠蛋白）链可抑制血红蛋白S（镰状血红蛋白）的聚合，并且在功能上可以替代β地中海贫血患者体内有缺陷或缺失的β-珠蛋白链。因此，寻找刺激胎儿血红蛋白生成的安全机制备受关注。以往研究表明，给予丁酸盐可选择性地刺激人胎儿珠蛋白基因的启动子，并导致发育中的胎儿、培养细胞及动物模型中γ-珠蛋白基因表达增加。
为了确定丁酸盐能否刺激人体胎儿血红蛋白的生成，我们对3例镰状细胞贫血患者（3至13岁）和3例β地中海贫血综合征患者（7至27岁）进行了短期静脉输注精氨酸丁酸盐治疗。药物持续输注2周或3周；初始剂量为每日每千克体重500毫克。在治疗前及治疗期间测定珠蛋白链比例、产生血红蛋白F的网织红细胞比例（F网织红细胞）以及γ-珠蛋白信使核糖核酸（mRNA）水平。
在所有6例患者中，胎儿血红蛋白合成比治疗前水平增加了6%至45%（P<0.01）。F网织红细胞比例增加了约两倍，γ-珠蛋白mRNA水平增加了两倍至六倍。γ-珠蛋白合成的增加使地中海贫血患者的珠蛋白链比例得到改善。对1例患者的治疗延长了7周，其血红蛋白水平从每分升4.7克升至10.2克（从每升2.9毫摩尔升至6.3毫摩尔）。副作用极小；1例患者血清转氨酶浓度短暂升高。
对于β血红蛋白病患者，天然脂肪酸丁酸盐可显著且迅速地增加胎儿血红蛋白生成，使其达到能改善β-珠蛋白疾病的水平。有必要对这类化合物进行进一步试验，以确定镰状细胞贫血或β地中海贫血患者的长期耐受性和疗效。
