FG4 IMPACT OF CYP2C9 AND CYP2C19 POLYMORPHISMS IN DRUG-INDUCED IDIOSYNCRATIC LIVER INJURY (DILI)

摘要

Background and aims: The general view on the pathogenesis of DILI is that parent compounds are rendered hepatotoxic during CYP450 metabolism which exhibits genetic polymorphisms. Beyond of anecdotal reports there are no data on CYP450 polymorphisms and their role in hepatotoxicity. We aimed to assess in a iarge series of Spanish DILI patients the prevalence of important allelic variants of CYP2C9 and CYP2C19 which are known to be involved in the metabolism of several hepatotoxic drugs.Methods: Genotyping of CYP2C9 (2 and 3) and CYP2C19 (2 and 3), was carried out in a total of 146 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. Results: In 146 patients with DILI (73 males, aged 15 - 82 years) associated to anti-infectives (29%), musculoskeletal (14%), central nervous system (13%) and cardiovascular drugs (12%), with jaundiced hepatitis (6%) requiring hospitalisation (%). CYP2C9 and CYP2C19 allele and genotype frequencies were in agreement with Hardy-Weinberg equilibrium. Fifty three patients (36%) carried one and 7 patients (5%) carried two CYP2C9 mutated alleles. 25 (17%) were found to carry one and 7(5%) carried two CYP2C19 mutated alleles. 13 patients carried variant CYP2C9 and CYP2C19 allele. No patients were homozygotes 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 allele did not differ in regard to clinical presentation of DILI, type of injury and outcome. Conclusions: Our results show that CYP2C9 and CYP2C19 genetic polymorphisms might not be a predictable potential risk factor for DILI.