Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug‐induced idiosyncratic liver injury (DILI)
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 45...
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| Published in: | British journal of pharmacology Vol. 150; no. 6; pp. 808 - 815 |
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| Main Authors: | , , , , , |
| Format: | Journal Article |
| Language: | English |
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Oxford, UK
Blackwell Publishing Ltd
01-03-2007
Nature Publishing Nature Publishing Group |
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| 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.
British Journal of Pharmacology (2007) 150, 808–815. doi:10.1038/sj.bjp.0707122 |
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| AbstractList | 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. 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. British Journal of Pharmacology (2007) 150, 808–815. doi:10.1038/sj.bjp.0707122 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. |
| Author | Pachkoria, K Crespo, E Cabello, M R Lucena, M I Ruiz‐Cabello, F Andrade, R J |
| AuthorAffiliation | 3 Departamento de Farmacología, Facultad de Farmacia, Universidad de Granada Granada , spain 1 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 2 S. Analisis Clínicos, Hospital Virgen de las Nieves Granada, Spain 4 Unidad de Hepatología, 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 |
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| Keywords | Drug Digestive system Enzyme Isozyme Toxicity Cytochrome P450 Liver CYP2C19 CYP2C9 hepatotoxicity genetic predisposition Genetics Polymorphism |
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The general view on the pathogenesis of drug‐induced idiosyncratic liver injury (DILI) is that parent compounds are rendered... The general view on the pathogenesis of drug-induced idiosyncratic liver injury (DILI) is that parent compounds are rendered hepatotoxic by metabolism, mainly... BACKGROUND AND PURPOSE: The general view on the pathogenesis of drug-induced idiosyncratic liver injury (DILI) is that parent compounds are rendered... |
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| SubjectTerms | Adolescent Adult Aged Aged, 80 and over Alleles Aryl Hydrocarbon Hydroxylases - genetics Biological and medical sciences Chemical and Drug Induced Liver Injury - enzymology Chemical and Drug Induced Liver Injury - genetics CYP2C19 CYP2C9 Cytochrome P-450 CYP2C19 Cytochrome P-450 CYP2C9 Female Gene Frequency genetic predisposition Genetic Variation hepatotoxicity Humans Liver - drug effects Liver - enzymology Liver - injuries Male Medical sciences Middle Aged Mixed Function Oxygenases - genetics Pharmacology. Drug treatments Polymorphism, Single Nucleotide Research Papers Risk Factors Spain |
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| Title | Genetic polymorphisms of CYP2C9 and CYP2C19 are not related to drug‐induced idiosyncratic liver injury (DILI) |
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