Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment.
Approximately 40% of human P450-dependent drug metabolism is carried out by polymorphic enzymes, which can cause abolished, quantitatively or qualitatively altered or enhanced drug 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. 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. Knowledge in this field has grown rapidly and can now be applied to both drug development and clinical practice. This is facilitated by the recent development of high-throughput methods for mutation detection and oligonucleotide chips array technology for the identification of a multitude of mutations in the genes encoding drug-metabolizing enzymes. The outcome will allow for safer and more efficient drug therapies.
Ingelman-Sundberg
M
M
Division of Molecular Toxicology, IMM, Karolinska Institutet, 171 77 Stockholm, Sweden.
Oscarson
M
M
McLellan
R A
RA
D000483:Alleles; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000097:blood / Q000235:genetics*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D019143:Evolution, Molecular; D006801:Humans; D011110:Polymorphism, Genetic; D017367:Selective Serotonin Reuptake Inhibitors / Q000378:metabolism*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D019389:Cytochrome P-450 CYP2D6; D003577:Cytochrome P-450 Enzyme System; D017367:Selective Serotonin Reuptake Inhibitors