S Farmacología Clínica and Unidad de Hepatogía, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Universidad de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain.
Liver Int. 2013 Oct;33(9):1378-85. doi: 10.1111/liv.12193. Epub 2013 May 23.
BACKGROUND & AIMS: Several pharmaceutical compounds have been shown to exert inhibitory effects on the bile salt export pump (BSEP) encoded by the ABCB11 gene. We analysed the combined effect on drug-induced liver injury (DILI) development of the ABCB11 1331T>C polymorphism and the presence of specific chemical moieties, with known BSEP inhibiting properties, in the causative drug.
Genotyping using a TaqMan 5' allelic discrimination assay was performed in 188 Spanish DILI patients, 219 healthy controls and 91 sex-, age- and drug-matched controls. A chemical structure analysis was performed for each individual causative drug.
The CC genotype was significantly associated with hepatocellular damage [odds ratio (OR) = 2.1, P = 0.001], particularly in NSAID DILI cases (OR = 3.4, P = 0.007). In addition, the CC genotype was found to be significantly linked to DILI development from drugs causing <50% BSEP inhibition (OR = 1.8, Pc = 0.011). Of the BSEP inhibitory chemical moieties, 59% of the causative drugs contained a carbocyclic system with at least one aromatic ring, corresponding to 61% of the total cases. The C allele was significantly more frequent in DILI cases containing this chemical moiety, which appear to be conditioned on the ABCB11 1331T>C polymorphism in the absence of other BSEP inhibitory structures.
Patients carrying the C allele in the ABCB11 1331T>C polymorphism are at increased risk of developing hepatocellular type of DILI, when taking drugs containing a carbocyclic system with aromatic rings.
几种药物化合物已被证明对 ABCB11 基因编码的胆汁盐输出泵（BSEP）具有抑制作用。我们分析了 ABCB11 1331T>C 多态性与导致肝损伤的药物（DILI）中特定化学结构的存在，这些化学结构具有已知的 BSEP 抑制特性，对药物性肝损伤（DILI）发展的联合作用。
使用 TaqMan 5'等位基因区分测定法对 188 名西班牙 DILI 患者、219 名健康对照者和 91 名性别、年龄和药物匹配的对照者进行基因分型。对每个个体的致病药物进行化学结构分析。
CC 基因型与肝细胞损伤显著相关[比值比（OR）=2.1，P=0.001]，特别是在 NSAID-DILI 病例中（OR=3.4，P=0.007）。此外，发现 CC 基因型与导致 BSEP 抑制<50%的药物引起的 DILI 发展显著相关（OR=1.8，Pc=0.011）。在 BSEP 抑制性化学结构中，59%的致病药物含有至少一个芳香环的碳环系统，占总病例的 61%。在含有这种化学结构的 DILI 病例中，C 等位基因明显更频繁，这似乎与 ABCB11 1331T>C 多态性有关，而与其他 BSEP 抑制结构无关。
携带 ABCB11 1331T>C 多态性 C 等位基因的患者在服用含有芳香环的碳环系统药物时，发生肝细胞型 DILI 的风险增加。
