Polymorphic Cytochromes P450 CYP2B6 and CYP2D6: Recent Advances on Single Nucleotide Polymorphisms Affecting Splicing

Recent work on functional polymorphisms in drug metabolizing cytochromes P450 CYP2B6 and CYP2D6 emphasizes the role of single nucleotide polymorphisms (SNPs) in non-consensus splicing elements such as exonic and intronic splicing enhancers. In the CYP2D6 gene the intron 6 SNP 2988G > A (allele *41) shifts the balance of spliced transcripts towards a variant that lacks exon 6. In the CYP2B6 gene, the 516G > T SNP, a marker of allele CYP2B6*6, encodes an amino acid change in exon 4 Q172Hbut also leads to increased amounts of a transcript lacking exons 4 to 6. In both cases aberrant splicing results in reduced amounts of functional transcript and reduced amounts of functional protein in the liver. Although expression of functional protein is only partially diminished, reduced activity phenotypes arise in homozygous genotypes or in compound heterozygotes carrying other severely affected alleles. We here describe the elucidation of these genetic polymorphisms and their mechanisms as well as their clinical relevance.