Perrine S P, Dover G H, Daftari P, Walsh C T, Jin Y, Mays A, Faller D V
Cancer Research Center, Boston University School of Medicine, Massachusetts 02118.
Br J Haematol. 1994 Nov;88(3):555-61. doi: 10.1111/j.1365-2141.1994.tb05073.x.
Butyrate and other short-chain fatty acids stimulate fetal globin gene expression and have potential for ameliorating the beta globin disorders. Butyrate, however, is rapidly metabolized in vivo and reaches only micromolar concentrations in plasma. We report here that a branched-chain derivative of butyrate, isobutyramide, increases gamma globin gene expression in cultured human erythroid progenitors in vitro and stimulates activity from a minimal gamma globin gene promoter linked to a reporter gene in stable and transient expression assays, with slightly less activity in these in vitro assays than butyrate. In vivo, administration of isobutyramide to anaemic adult baboons rapidly stimulates fetal globin synthesis and F-reticulocyte production. Plasma concentrations at millimolar levels are achieved after a single intravenous or oral dose (500-600 mg/kg), and these concentrations are maintained for 9.5-10.5 h. These results indicate that although isobutyramide has slightly less activity than butyrate in vitro in enhancing fetal globin expression at the cellular and molecular level, its prolonged in vivo half-life may provide superior activity as a therapeutic agent for reactivating fetal globin gene expression in vivo.
丁酸和其他短链脂肪酸可刺激胎儿珠蛋白基因表达，具有改善β珠蛋白疾病的潜力。然而，丁酸在体内会迅速代谢，血浆中仅达到微摩尔浓度。我们在此报告，丁酸的一种支链衍生物异丁酰胺，在体外可增加培养的人类红系祖细胞中γ珠蛋白基因的表达，并在稳定和瞬时表达试验中刺激与报告基因相连的最小γ珠蛋白基因启动子的活性，在这些体外试验中的活性略低于丁酸。在体内，给贫血成年狒狒施用异丁酰胺可迅速刺激胎儿珠蛋白合成和F-网织红细胞生成。单次静脉注射或口服剂量（500 - 600 mg/kg）后可达到毫摩尔水平的血浆浓度，且这些浓度可维持9.5 - 10.5小时。这些结果表明，尽管异丁酰胺在体外增强胎儿珠蛋白表达方面在细胞和分子水平上的活性略低于丁酸，但其延长的体内半衰期可能使其作为一种治疗剂在体内重新激活胎儿珠蛋白基因表达方面具有更优越的活性。
