Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children
Favorable effect of 4-phenylacetate on liver functions attributable to enhanced bile salt export pump expression in ornithine transcarbamylase-deficient children
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DOI：
10.1016/j.ymgme.2010.02.008
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发表时间：
2010-06-01
影响因子：
3.8
通讯作者：
Hayashi, Hisamitsu
中科院分区：
文献类型：
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作者：
Nagasaka, Hironori;Yorifuji, Tohru;Hayashi, Hisamitsu
4-苯丁酸盐（4-PB）治疗高氨血症已被用于尿素循环缺陷患者。我们最近使用动物和培养细胞的实验结果强烈表明，该试剂增强了胆盐输出泵/ATP结合盒B11（BSEP/ABCB 11）的功能，促进胆汁酸从肝细胞排泄到胆小管，尽管尚未在人体中得到证实。考虑到4-PB在肝脏中容易转化为4-苯乙酸（4-PA），4-PB的这种作用可能通过4-PA发生。我们回顾性分析了4-PA对三名接受4-PA治疗的鸟氨酸转氨甲酰酶（OTC）缺乏症女童肝功能的影响。其中2例仅在高氨血症发作期接受4-PA静脉给药;其余1例在间歇期接受口服。4-PA给药后不久，血清总胆汁酸水平下降到治疗前的一半或三分之一，但在4-PA停药后一个月内恢复到基础水平。胆汁淤积的其他血清参数，如γ-谷氨酰转移酶也显著降低。同时，丙氨酸氨基转移酶和天冬氨酸氨基转移酶水平显著降低。肝脏样品的Western印迹分析显示，4-PA给药增强了肝细胞膜部分中的BSEP/ABCB 11蛋白表达，尽管肝脏BSEP/ABCB 11信使RNA水平保持不变。这些结果表明，4-PA增强肝脏BSEP/ABCB 11功能，从而改善OTC缺陷儿童的肝功能。对于需要增强BSEP功能的肝脏疾病的治疗，4-PA可能是一种候选药物。(C)2010年爱思唯尔公司All rights reserved.
4-Phenylbutyrate (4-PB) acting against hyperammonemia has been administered to patients with urea cycle defects. Results of our recent experiments using animals and cultured cells strongly suggest that this agent enhances the function of bile salt export pump/ATP binding cassette B11 (BSEP/ABCB11) promoting bile acid excretion from hepatocytes to bile canaliculi, although it has not been confirmed in humans. Considering that 4-PB is converted easily into 4-phenylacetate (4-PA) in the liver, such an effect of 4-PB might occur through 4-PA. We performed retrospective analyzes of the effects of 4-PA on the liver functions of three ornithine transcarbamylase (OTC)-deficient female children receiving 4-PA. Two of the three received intravenous administration of 4-PA only at episodic periods of hyperammonemia; the remaining one received it orally at intercurrent periods. Soon after 4-PA administration, the serum total bile acid level was decreased to one-half or one-third of pre-treatment levels, but it returned to the basal levels within one month after 4-PA discontinuation. Other serum parameters for cholestasis such as gamma-glutamyl transferase also decreased markedly. Concomitantly, alanine aminotransferase and aspartate amino transferase levels decreased significantly. Western blot analyzes of the liver samples revealed that the 4-PA administration enhanced BSEP/ABCB11 protein expressions in the membranous fraction of liver cells, although the liver BSEP/ABCB11 messenger RNA level remained unchanged. These results suggest that 4-PA enhanced liver BSEP/ABCB11 function and thereby improved liver functions in OTC-deficient children. For treatment of liver disorders requiring enhancement of BSEP function, 4-PA might be a candidate. (C) 2010 Elsevier Inc. All rights reserved.