Cytochrome P450: genotype to phenotype

The cytochromes P450 comprise a family of enzymes that are responsible for around three-quarters of all drug metabolism reactions that occur in human populations. Many isoforms of cytochrome P450 exist but most reactions are undertaken by CYP2C9, CYP2C19, CYP2D6 and CYP3A4. This brief review focusses on the first three isozymes which exhibit polymorphism of phenotype. If there is a wide variation in drug metabolising capacity within the population, this may precipitate clinical consequences and influence the drug treatment of patients. Such problems range from a lack of efficacy to unanticipated toxicity. In order to minimise untoward events and personalise a patient's treatment, efforts have been made to discover an individual's drug metabolism status. This requires knowledge of the subject's phenotype at the time of clinical treatment. Since such testing is difficult, time-consuming and costly, the simpler approach of genotyping has been advocated. However, the correlation between genotype and phenotype is not good, with values of up to 50% misprediction being reported. Genotype-assisted forecasts cannot therefore be used with confidence to replace actual phenotype measurements. Obfuscating factors discussed include gene splicing, single nucleotide polymorphisms, epigenetics and microRNA, transcription regulation and multiple gene copies.