TY - JOUR T1 - A New CYP3A5 Variant, <em>CYP3A5*11</em>, Is Shown to Be Defective in Nifedipine Metabolism in a Recombinant cDNA Expression System JF - Drug Metabolism and Disposition JO - Drug Metab Dispos SP - 67 LP - 71 DO - 10.1124/dmd.106.012310 VL - 35 IS - 1 AU - Su-Jun Lee AU - Ilse P. van der Heiden AU - Joyce A. Goldstein AU - Ron H. N. van Schaik Y1 - 2007/01/01 UR - http://dmd.aspetjournals.org/content/35/1/67.abstract N2 - A new CYP3A5 variant, CYP3A5*11, was found in a white European subject by DNA sequencing. The CYP3A5*11 allele contains a single nucleotide polymorphism (SNP) (g.3775A&gt;G) in exon 2, which results in a Tyr53Cys substitution, and a g.6986A&gt;G splice change, the latter SNP previously reported in the defective CYP3A5*3 allele. However, the CYP3A5*3 is not a null allele because this variant is associated with leaky splicing, resulting in small amounts of functional protein still being produced. Therefore, we constructed a cDNA coding for the newly identified CYP3A5.11 protein by site-directed mutagenesis, expressed it in Escherichia coli, and partially purified it. Whereas bacteria transformed with wild-type CYP3A5*1 cDNA expressed predominantly cytochrome P450 (P450), those transfected with CYP3A5*11 expressed a significant amount of denatured cytochrome P420 in addition to P450, suggesting the protein to be unstable. CYP3A5.11 exhibited a 38% decrease in the Vmax for nifedipine metabolism, a 2.7-fold increase in the Km, and a 4.4-fold decrease in the CLint of nifedipine compared with CYP3A5.1. A polymerase chain reaction-restriction fragment length polymorphism genotyping procedure was developed and used to genotype DNA of 500 white individuals for CYP3A5*11. No additional examples of this allele were identified. In summary, individuals carrying the rare CYP3A5*11 allele are predicted to have lower metabolism of CYP3A5 substrates than individuals expressing CYP3A5*3. The American Society for Pharmacology and Experimental Therapeutics ER -