Two Novel CYP2D6*10 Haplotypes As Possible Causes of a Poor Metabolic Phenotype in Japanese

During the course of sequencing for the CYP2D6 gene, we found a novel single nucleotide polymorphism of g.3318G>A (E383K) associated with CYP2D6*10 , termed as CYP2D6*72. We also found a g.1611T>A (F120I) in the CYP2D6*49 , which was previously identified as a CYP2D6*10 -associated allele in an independent Japanese population. To clarify the effects of these novel CYP2D6*10 haplotypes on the functions of CYP2D6, kinetic analysis for dextromethorphan O -demethylation was performed using the Escherichia coli expression system and human liver microsomes. The V max / K m values for dextromethorphan O -demethylation catalyzed by recombinant CYP2D6 forms encoded by CYP2D6*10 , CYP2D6*49 , and CYP2D6*72 were 3.0, 0.5, and 1.3%, respectively, compared with that catalyzed by CYP2D6.1. Liver microsomes from a human subject genotyped as CYP2D6*10/*49 also showed a reduced dextromethorphan O -demethylase activity. CYP2D6.49 formed a 7-hydroxydextromethorphan, with a roughly similar V max / K m value to that of O -demethylation. These results suggest that these two CYP2D6*10 haplotypes are possible causes of interindividual variation in the activities and the substrate specificity of CYP2D6.