PIII‐32

BACKGROUND A novel CYP2D7 brain‐specific protein capable of metabolizing codeine has been described. The purpose of this study was to examine CYP2D7 splicing in human brain and liver, and to investigate tissue‐specific expression of the CYP2D7 splice variant encoding the novel protein. We also determined the frequencies of a frame‐shift‐reverting (138delT) and a stop codon‐reverting (g.14408G>C) SNP in CYP2D7 , prerequisites for translation into functional protein. METHODS CYP2D7 and CYP2D6 full‐length brain and liver cDNAs were cloned and sequenced. Splice variants were analyzed by RT‐PCR in pre‐ and postnatal brain and liver samples. A total of 285 DNA samples covering major ethnicities were genotyped for CYP2D7 138delT and g.14408G>C with gene specific assays. Information theory‐based analyses were employed to characterize splice donor and acceptor sites. RESULTS 14 CYP2D7 and 13 CYP2D6 splice variants were detected. Transcript containing partial intron 6 was a minor CYP2D7 variant and was found in brain and liver. 138delT and g.14408G>C allowing translation into the novel CYP2D7 protein were absent in any subject. Usage of cryptic splice sites within exon 6 and intron 6 explained the generation of multiple CYP2D6 and CYP2D7 variants and preferential retention of part of intron 6 by CYP2D7. CONCLUSION Partial retention of CYP2D7 intron 6 was independent of 138delT and occurred in all brain and liver tissues tested. CYP2D7 is unlikely to encode functional transcripts in most individuals. Clinical Pharmacology & Therapeutics (2005) 79 , P67–P67; doi: 10.1016/j.clpt.2005.12.240