Pachkoria K, Lucena M I, Ruiz-Cabello F, Crespo E, Cabello M R, Andrade R J
Servicio de Farmacología Clínica, Grupo de Estudio para las Hepatopatías Asociadas a Medicamentos, Co-ordinating Centre, Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Campus Universitario de Teatinos s/n, Málaga, Spain.
Br J Pharmacol. 2007 Mar;150(6):808-15. doi: 10.1038/sj.bjp.0707122. Epub 2007 Feb 5.
The general view on the pathogenesis of drug-induced idiosyncratic liver injury (DILI) is that parent compounds are rendered hepatotoxic by metabolism, mainly by cytochrome (CYP) 450, although other metabolic pathways can contribute. Anecdotal reports suggest a role of CYP 450 polymorphisms in DILI. We aimed to assess in a series of Spanish DILI patients the prevalence of important allelic variants of CYP2C9 and CYP2C19, known to be involved in the metabolism of several hepatotoxic drugs.
Genotyping of CYP2C9 (()2, ()3) and CYP2C19 (()2 and ()3), was carried out in a total of 28 and 32 patients with a well established diagnosis of DILI. CYP2C9 and CYP2C19 variants were analysed in genomic DNA by means of PCR-FRET and compared with previous findings in other Caucasian populations.
CYP2C9 and CYP2C19 allele and genotype frequencies were in agreement with Hardy-Weinberg equilibrium. Fourteen patients (50%) were heterozygous and 1(4%) found to be compound heterozygous for the CYP2C9 allele. Seven (22%) were found to carry one and 1(3%) carried two CYP2C19 mutated alleles. No patients were homozygous for (*)3 allele. The distribution of both CYP2C9 and CYP2C19 allelic variants in DILI patients were similar to those in other Caucasian populations. Patients with variant and those with wild-type alleles did not differ in regard to clinical presentation of DILI, type of injury and outcome.
We find no evidence to support CYP2C9 and CYP2C19 genetic polymorphisms as predictable potential risk factors for DILI.
药物性特异质性肝损伤（DILI）发病机制的普遍观点是，母体化合物通过代谢（主要是细胞色素（CYP）450介导）而具有肝毒性，尽管其他代谢途径也可能起作用。轶事报道提示CYP 450基因多态性在DILI中起作用。我们旨在评估一系列西班牙DILI患者中已知参与多种肝毒性药物代谢的CYP2C9和CYP2C19重要等位基因变异的患病率。
对总共28例和32例确诊为DILI的患者进行CYP2C9（（）2，（）3）和CYP2C19（（）2和（）3）基因分型。通过PCR-FRET分析基因组DNA中的CYP2C9和CYP2C19变异，并与其他白种人群的先前研究结果进行比较。
CYP2C9和CYP2C19等位基因及基因型频率符合哈迪-温伯格平衡。14例患者（50%）为CYP2C9等位基因杂合子，1例（4%）为复合杂合子。7例（22%）携带1个CYP2C19突变等位基因，1例（3%）携带2个CYP2C19突变等位基因。无患者为（*）3等位基因纯合子。DILI患者中CYP2C9和CYP2C19等位基因变异的分布与其他白种人群相似。携带变异等位基因的患者与携带野生型等位基因的患者在DILI的临床表现、损伤类型和转归方面无差异。
我们没有发现证据支持CYP2C9和CYP2C19基因多态性是DILI可预测的潜在危险因素。
