Lang Carmen, Meier Yvonne, Stieger Bruno, Beuers Ulrich, Lang Thomas, Kerb Reinhold, Kullak-Ublick Gerd A, Meier Peter J, Pauli-Magnus Christiane
Division of Clinical Pharmacology and Toxicology, University Hospital Zurich, Switzerland.
Pharmacogenet Genomics. 2007 Jan;17(1):47-60. doi: 10.1097/01.fpc.0000230418.28091.76.
Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms.
ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay.
Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced cholestasis) and G855R (drug-induced cholestasis); ABCB4: I764L (drug-induced cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P<0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional.
In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced cholestasis. Genotyping of selected patients with acquired cholestasis might help to identify individuals with a genetic predisposition.
越来越多的证据表明，肝细胞外排转运体胆盐输出泵（BSEP，ABCB11）和多药耐药蛋白3（MDR3，ABCB4）的基因决定性功能障碍在药物性肝损伤的发生发展中起病理生理作用。因此，本研究的目的是描述药物性肝损伤患者ABCB11和ABCB4基因变异的程度，并对新检测到的ABCB11突变和多态性进行体外功能表征。
对23例药物性胆汁淤积患者和13例药物性肝细胞损伤患者的ABCB11和ABCB4进行测序。95名健康白种人作为对照组。将参考和突变型BSEP在Sf9细胞中表达，并通过快速过滤测定法测量[H]-牛磺胆酸盐的ATP依赖性转运。
四个高度保守的非同义突变是药物性肝损伤特有的[ABCB11：D676Y（药物性胆汁淤积）和G855R（药物性胆汁淤积）；ABCB4：I764L（药物性胆汁淤积）和L1082Q（药物性肝细胞损伤）]。此外，ABCB11第13外显子的多态性（V444A）与肝脏BSEP表达降低有关，在药物性胆汁淤积患者中比在药物性肝细胞损伤患者和健康对照中更常见（药物性胆汁淤积患者、药物性肝细胞损伤患者和健康对照中分别为76%、50%和59%；P<0.05）。V444A和D676Y BSEP构建体的体外转运活性相似，而G855R突变无功能。
总之，我们的数据支持ABCB11和ABCB4突变及多态性在药物性胆汁淤积中的作用。对选定的获得性胆汁淤积患者进行基因分型可能有助于识别具有遗传易感性的个体。
