title: Identification and characterization of a defective CYP3A4 genotype in a kidney transplant patient with severely diminished tacrolimus clearance.
abstract: 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.
authors.affiliation: Institute for Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: A N
authors.initials: AN
authors.lastname: Werk
authors.affiliation: Department of Nephrology, University Hospital Klinikum rechts der Isar of the Technical University of Munich, Munich, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Lefeldt
authors.affiliation: Institute for Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Bruckmueller
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Hemmrich-Stanisak
authors.affiliation: Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Franke
authors.affiliation: Department of Nephrology, University Hospital Klinikum rechts der Isar of the Technical University of Munich, Munich, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Roos
authors.affiliation: Department of Nephrology, University Hospital Klinikum rechts der Isar of the Technical University of Munich, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Küchle
authors.affiliation: Department of Nephrology, University Hospital Klinikum rechts der Isar of the Technical University of Munich, Munich, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Steubl
authors.affiliation: Department of Nephrology, University Hospital Klinikum rechts der Isar of the Technical University of Munich, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Schmaderer
authors.affiliation: 1] Institute of Pathology Hamburg-West, Hamburg, Germany [2] Institute for Pathology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: J H
authors.initials: JH
authors.lastname: Bräsen
authors.affiliation: Department of Nephrology, University Hospital Klinikum rechts der Isar of the Technical University of Munich, Munich, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Heemann
authors.affiliation: Institute for Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein Campus Kiel, Kiel, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Cascorbi
authors.affiliation: Department of Nephrology, University Hospital Klinikum rechts der Isar of the Technical University of Munich, Munich, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Renders
mesh_terms: D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D056945:Hep G2 Cells; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*; D016030:Kidney Transplantation; D008297:Male; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D016559:Tacrolimus / Q000493:pharmacokinetics*; D014162:Transfection; D055815:Young Adult
chemical_list: D007166:Immunosuppressive Agents; C510164:CYP3A5 protein, human; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D016559:Tacrolimus