Pharmacogenetics: the molecular genetics of CYP2D6 dependent drug metabolism

Genetic variation of drug metabolising enzymes has been recognised as one of the major causes of the inter-individual variability to drug response. The vast majority of drugs are degraded via a small number of metabolic pathways, mainly by microsomal P-450 enzymes localised in the liver and, to a minor extent, in the small intestine. Of these, CYP3A4 is the isozyme involved in the metabolism of most of the clinically useful drugs (50%). This is followed by CYP2D6 (20%), CYP2C9 and CYP2C19 (15%). In addition, minor pathways are catalysed by CYP2E1, CYP1A2, CYP2A6 and unidentified P-450s. Almost 40% of human P-450 dependent drug metabolism is carried out by genetically polymorphic enzymes. Polymorphisms generated by mutations in the genes for these enzymes cause quantitatively or qualitatively altered enzyme expression or activity through multiple molecular mechanisms. While CYP3A4 genetic polymorphisms are just beginning to be unraveled, extensive studies on the CYP2D6 gene over the last decade have identified at least 53 alleles. Of these, more than 20 of them are known to significantly alter the metabolism of CYP2D6 substrates.

This article reviews the information derived from various studies over the past decade and explains the molecular basis of functional differences in CYP2D6 variants, especially with respect to inter-ethnic differences and their clinical implications.

CYP2D6 activity ranges from complete absence to ultra-rapid metabolism. Large inter-individual and inter-ethnic variability exists in the activity of the enzyme, and consequently in the disposition of drugs undergoing oxidative metabolism.

Pharmacokinetic differences resulting from these polymorphisms show potentially important clinical consequences.