Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug‐induced idiosyncratic liver injury (DILI)

Abstract

Background and purpose: 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. Experimental approach: 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. Key results: 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. Conclusions and Implications: We find no evidence to support CYP2C9 and CYP2C19 genetic polymorphisms as predictable potential risk factors for DILI.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME

“…It was due to their polymorphic nature that it could easily be conceived that a specific polymorphic variant could alter drug metabolism and cause a rare form of DILI. These associations were proved invalid when no association was seen in a Spanish registry of DILI in cases with drugs metabolized by these enzymes (Pachkoria et al 2007). In fact, a large number of studies looking at associations with CYP enzyme particular polymorphisms follow a similar route or only identify relatively weak associations.…”

Risk Factors for Idiosyncratic Drug-Induced Liver Injury

“…The Spanish registry failed to show significant enrichment of CYP2C9 and CYP2C19 polymorphisms in a well-characterized cohort of DILI patients. 111 …”

Analysis of IL-10, IL-4 and TNF-α polymorphisms in drug-induced liver injury (DILI) and its outcome

“…Venous blood was obtained in tubes containing K3-EDTA from each subject and DNA was extracted as described previously [23]. Peripheral eosinophilia was defined as more than the upper reference limit for percentage of eosinophils.…”