Trends in Pharmacological Sciences
Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future
Section snippets
Cytochrome P450 25 years ago
When TiPS was first published in 1979 the debate regarding whether one or more forms of P450 existed had recently been resolved. In 1978, the first P450 was purified to homogeneity, now termed CYP2B4, and the first P450 (CYP2B1 from rat) was cloned three years later. Attendees of the 5th Microsomes and Drug Oxidation (MDO) meeting in Tokyo were surprised and silent when the first cDNA sequence was presented by Fujii-Kuriyama in the summer of 1981. At that time it was difficult to foresee the
Human cytochrome P450 genes
The milestone of the completion of the sequence of the human genome allowed David Nelson to provide evidence for the presence of 57 different active genes encoding P450 enzymes (http://drnelson.utmem.edu/CytochromeP450.html) and a similar number (58) of pseudogenes [8]. This number of active genes is much smaller than that observed in rice (323 genes), Thale cress (249 genes) or the mouse (102 genes) but is similar to that observed in the dog (54 genes). The major P450 forms that are important
Polymorphism of P450 genes
All genes encoding P450 enzymes in families 1–3 are polymorphic. The functional importance of the variant alleles, however, differs and the frequencies of their distribution in different ethnic groups also differ. Updated information can be found on the Human CYPallele Nomenclature Website (http://www.imm.ki.se/cypalleles). Polymorphic enzymes (in particular CYP2C9, CYP2C19 and CYP2D6) mediate ∼40% of P450-mediated drug metabolism, which makes drug dosing problematic. In general, four
The background to the major discoveries in the field of P450
Inter-individual differences in response to a xenobiotic was probably described first by Pythagoras in 510 bc when he noted that some, but not all, individuals develop haemolytic anaemia in response to fava bean ingestion. In a report by Gorrod and Oxon in 1902 [12], a genetic component was suggested to be involved in biochemical processes where the cause of inter-individual differences in ADRs was due to enzyme deficiencies. Thirty years later in 1932, Snyder [13] described the first
Clinical relevance of cytochrome P450 polymorphism
Pharmacogenetics today, to a great extent, deals with genes encoding drug transporters, drug-metabolizing enzymes and drug targets. There is no doubt that the polymorphism of metabolizing enzymes, and in particular that of cytochromes P450s, has the greatest effect on inter-individual variability of drug response, as evidenced by many studies 2, 3, 4, 5, 6, 7. These polymorphisms affect the response of individuals to drugs used in the treatment of depression, psychosis, cancer, cardiovascular
Future aspects
It is to be assumed that the major allelic variants of P450 genes of clinical importance have now been identified. However, further genetic reasons that underlie variable P450 expression might remain to be identified in other genes encoding, for example, proteins with regulatory functions such as transcription factors. Furthermore, RNA-regulating proteins might to be relevant and add to the complexity of the field. In addition, P450 expression polymorphism might not only exist at the genomic
Acknowledgements
I am much indebted to Julia Kirchheiner, Michel Eichelbaum, Joyce Goldstein, Urs Meyer, Mikael Oscarson, Kathryn Phillips, Folke Sjöqvist and Wendell Weber for providing me with preprints, reprints and/or important background information, and to Inger Johansson for critically reading the manuscript. The work in my laboratory is supported by grants from the Swedish Research Council and from NIH (NIGMS 1-R01 GM60548–01A2).
References (84)
Clinical application of pharmacogenetics
Trends Mol. Med.
(2001)- et al.
Plasma levels of monomethylated tricyclic antidepressants during treatment with imipramine-like compounds
Life Sci.
(1967) Polymorphic hydroxylation of debrisoquine in man
Lancet
(1977)- et al.
Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification
Lancet
(1990) Disassociation between debrisoquine hydroxylation phenotype and genotype among Chinese
Lancet
(1989)Molecular basis for rational megaprescribing in ultrarapid hydroxylators of debrisoquine
Lancet
(1993)Polymorphic human cytochrome P450 enzymes: an opportunity for individualized drug treatment
Trends Pharmacol. Sci.
(1999)Isolation and characterization of human liver cytochrome P450 2C19: correlation between 2C19 and S-mephenytoin 4′-hydroxylation
Arch. Biochem. Biophys.
(1993)The major genetic defect responsible for the polymorphism of S-mephenytoin metabolism in humans
J. Biol. Chem.
(1994)Characterization and PCR-based detection of a CYP2A6 gene deletion found at a high frequency in a Chinese population
FEBS Lett.
(1999)