Drug‐Metabolising Enzymes: Genetic Polymorphisms


Polymorphism in drug‐metabolising enzymes is of great importance for interindividual differences in drug therapy. Variant genes causing increased, decreased or abolished drug metabolism influences the drug response and risk for adverse drug reactions. The genetic alterations include single‐nucleotide polymorphisms, ins/del and gene copy number variations. Of particular importance are the cytochrome P450 enzymes responsible for the metabolism of the majority of clinically important drugs. This variability is now emphasised during drug development and of importance for routine drug prescription. Several different drugs contain pharmacogenomic labels where genotyping before prescription is mandatory or recommended. Predictive genotyping of drug‐metabolising genes can thus help to design individualised, safer and more efficient drug therapies.

Key Concepts:

  • The majority of drug metabolism is carried out by cytochrome P450 enzymes.

  • The polymorphic cytochrome P450 enzymes account for 40% of the phase I drug metabolism.

  • The major phenotypes with respect to drug metabolism are poor metabolisers (PMs), intermediate metabolisers (IMs), extensive metabolisers (EMs) and ultrarapid metabolisers (UMs).

  • There are large interethnic differences in the drug metabolism caused by genetic factors.

  • The toxicity of some anticancer drugs, and antibiotics can be predicted by the occurrence of particular genes encoding drug‐metabolising enzymes.

  • The effective dose of clopidogrel, warfarin, tricyclic antidepressants, tamoxifen and some antipsychotics is determined by the P450 polymorphism.

  • Irenotecan and mercaptopurine toxicity is dependent on UGT1A1 and TPMT polymorphism, respectively.

  • 85% of the pharmacogenomic drug labels refer to genes encoding drug‐metabolising enzymes, in particular cytochrome P450.

Keywords: cytochrome P‐450; adverse drug reactions; ultrarapid metabolism; gene duplication; poor metabolisers

Figure 1.

Distribution of activity among drug‐metabolising enzymes as a function of genetic variation. PM, poor metabolisers; IM, intermediate metabolisers; EM, efficient metabolisers; UM, ultrarapid metabolisers; SNP, single‐nucleotide polymorphism.



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Web Links

Aldehyde Dehydrogenase 2 Family (Mitochondrial) (ALDH2); Locus ID: 217. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=217

Aldehyde Dehydrogenase 2 Family (Mitochondrial) (ALDH2); MIM number: 100650. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?100650

Cytochrome P450, Subfamily IIA (Phenobarbital‐inducible), Polypeptide 6 (CYP2A6); Locus ID: 1548. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1548

Cytochrome P450, Subfamily IIA (Phenobarbital‐inducible), Polypeptide 6 (CYP2A6); MIM number: 122720. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?122720

Cytochrome P450, Subfamily IID (Debrisoquine, Sparteine, etc., ‐Metabolizing), Polypeptide 6 (CYP2D6); Locus ID: 1565. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=1565

Cytochrome P450, Subfamily IID (Debrisoquine, Sparteine, etc., ‐Metabolizing), Polypeptide 6 (CYP2D6); MIM number: 124030. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?124030

Glutathione S‐Transferase M1 (GSTM1); Locus ID: 2944. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2944

Glutathione S‐Transferase M1 (GSTM1); MIM number: 138350. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim? 138350

Human Cytochrome P450 (CYP) Allele Nomenclature Committee. Gives an update of most polymorphic human cytochrome P450 genes and their nomenclature. http://www.imm.ki.se/CYPalleles/

Pharmacogenomics Knowledge Base. http://www.pharmgkb.org/

Thiopurine Methyltransferase (TPMT); Locus ID: 7172. LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=7172

Thiopurine Methyltransferase (TPMT); MIM number: 187680. OMIM: http://www.ncbi.nlm.nih.gov/htbin‐post/Omim/dispmim?187680

Valid Genomic Biomarkers in the Context of Approved Drug Labels. http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/ucm083378.htm

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Ingelman‐Sundberg, Magnus(Nov 2011) Drug‐Metabolising Enzymes: Genetic Polymorphisms. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006015.pub2]