RESUMEN
Cytochrome P450 3A4 (CYP3A4) is involved in the metabolism of more drugs in clinical use than any other foreign compound-metabolizing enzyme in humans. Recently, increasing evidence has been found showing that variants in the CYP3A4 gene have functional significance and--in rare cases--lead to loss of activity, implying tremendous consequences for patients. This review article highlights the functional consequences of all CYP3A4 variants recognized by the Human Cytochrome P450 (CYP) Allele Nomenclature Database.
Asunto(s)
Citocromo P-450 CYP3A/genética , Citocromo P-450 CYP3A/metabolismo , Farmacogenética , Polimorfismo Genético , Interacciones Farmacológicas , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/enzimología , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/genética , Genotipo , Humanos , Seguridad del Paciente , Farmacocinética , Fenotipo , Medicina de Precisión , Medición de Riesgo , Factores de RiesgoRESUMEN
Cytochrome P450 3A4 (CYP3A4) is a major drug-metabolizing enzyme that is widely investigated. So far, no homozygous inactive variant has been described. We report on a 19-year-old kidney transplant patient suffering from Alport syndrome, who experienced unexpected high tacrolimus plasma trough levels during immunosuppressant therapy. Because nonadherence, liver failure, or drug-drug interactions could be excluded, we hypothesized a diminished metabolism of the drug caused by mutations in the main detoxification enzyme, CYP3A4. Exome sequencing revealed a novel single-nucleotide polymorphism (c.802C>T) resulting in a premature stop codon in CYP3A4 exon 5. Accordingly, no CYP3A4 protein could be detected in kidney biopsy tissue, and there was lack of expression in HepG2 cells transiently transfected with the mutated CYP3A4. In addition, the patient harbored inactive CYP3A5*3, resulting in loss of function of the entire CYP3A locus, explaining the deteriorated tacrolimus clearance. This is, to our knowledge, the first case of a complete failure of CYP3A4 in humans.