Polymorphism of cytochrome P450 and xenobiotic toxicity.

The majority of human P450-dependent xenobiotic metabolism is carried out by polymorphic enzymes which can cause abolished, quantitatively or qualitatively altered or enhanced metabolism. The latter situation is due to stable duplication, multiduplication or amplification of active genes, most likely in response to dietary components that have resulted in a selection of alleles with multiple non-inducible genes. An updated list of variant CYP alleles is present at the Home Page of the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http://www.imm.ki.se/CYPalleles/). Several examples exist where subjects carrying certain alleles suffer from a lack of drug efficacy due to ultrarapid metabolism or, alternatively, adverse effects from the drug treatment due to the presence of defective alleles. Dosage requirements for several commonly used drugs that have a narrow therapeutic range can differ more than 20-fold dependent on the genotype or the enzyme expression status. By contrast, carcinogen metabolising cytochrome P450s are less polymorphic and no firm relationships have been established linking increased risk for cancer with any specific P450 polymorphism. In the present overview recent aspects of cytochrome P450 polymorphism and xenobiotic toxicity are discussed.

[1]  M. Ingelman-Sundberg.  Pharmacogenetics: an opportunity for a safer and more efficient pharmacotherapy , 2001, Journal of internal medicine.

[2]  H. Klenk,et al.  Identification and functional characterization of eight CYP3A4 protein variants. , 2001, Pharmacogenetics.

[3]  R. Tyndale,et al.  Duplications and defects in the CYP2A6 gene: identification, genotyping, and in vivo effects on smoking. , 2000, Molecular pharmacology.

[4]  M. Ingelman-Sundberg,et al.  Inherited amplification of an active gene in the cytochrome P450 CYP2D locus as a cause of ultrarapid metabolism of debrisoquine. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[5]  M. Ingelman-Sundberg,et al.  Human cytochrome P450 (CYP) genes: recommendations for the nomenclature of alleles. , 2000, Pharmacogenetics.

[6]  S. Imaoka,et al.  The decreased in vivo clearance of CYP2D6 substrates by CYP2D6*10 might be caused not only by the low-expression but also by low affinity of CYP2D6. , 2000, Archives of biochemistry and biophysics.

[7]  M. Ingelman-Sundberg,et al.  Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment. , 1999, Trends in pharmacological sciences.

[8]  M. Relling,et al.  Pharmacogenomics: translating functional genomics into rational therapeutics. , 1999, Science.

[9]  M Ingelman-Sundberg,et al.  Identification and tissue distribution of the novel human cytochrome P450 2S1 (CYP2S1). , 2001, Biochemical and biophysical research communications.

[10]  G. Granneman,et al.  Use of In Vitro and In Vivo Data to Estimate the Likelihood of Metabolic Pharmacokinetic Interactions , 1997, Clinical pharmacokinetics.

[11]  M Ingelman-Sundberg,et al.  A combination of mutations in the CYP2D6*17 (CYP2D6Z) allele causes alterations in enzyme function. , 1997, Molecular pharmacology.

[12]  M. Oscarson.  Genetic polymorphisms in the cytochrome P450 2A6 (CYP2A6) gene: implications for interindividual differences in nicotine metabolism. , 2001, Drug metabolism and disposition: the biological fate of chemicals.

[13]  Ann Daly,et al.  Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression , 2001, Nature Genetics.