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Biochemistry

Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications.

Bernard, SN et al., 2006. Oncologist 11(2): 126-35.

Abstract

DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide inter-individual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic variants of the CYP2D6 isozyme that result in varying levels of metabolic activity are of clinical importance in some settings. The exact nature of the clinical effect caused by polymorphisms of the gene depends on the drug in question and the specific variant alleles expressed, as individual variants result in differing phenotypes with a range of levels of enzymatic activity. Compromised drug efficacy due to CYP2D6 variation has been documented with a variety of agents, and this review considers a number of examples, including the 5-HT(3)-receptor antagonists, which are used in oncology supportive care for the prophylaxis of nausea and vomiting. CYP2D6 is involved in the metabolism of all of the most commonly available agents, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism. Significant interethnic differences in CYP2D6 allele frequencies have been demonstrated from studies across many countries. However, incidences of polymorphisms in the U.S. population have been challenging to characterize because of the country's wide ethnic diversity. The CYP2D6 polymorphism may become more important as robust clinical tests become widely available and as the use of multiple medications and the attendant risk for drug-drug interactions increases.

Journal Link  | PMID

Comment

This review has three learning objectives, and it achieves them well. in addition to a general introduction these include understanding the four genotypes for CYP2D6 polymorphisms, the potential effects of CYP2D6 polymorphism on the efficacy and safety for drugs metabolized via this enzyme, and a useful listing of the ethnic groups that are most frequently affected by genetic variation of the CYP2D6 enzyme.  Although focused on the this single enzyme and its variants, this article is a good introduction/review for other clinical important enzymes and proteins encoded by polymorphic genes.

Assessment of CYP1A2 activity in clinical practice: Why, how, and when?

Faber, MS et al., 2005. Basic Clin Pharmacol Toxicol. 97(3):125-134.

Abstract

The cytochrome P450 enzyme CYP1A2 mediates the rate-limiting step in the metabolism of many drugs including theophylline, clozapine, and tacrine as well as in the bioactivation of procarcinogens. CYP1A2 activity shows both pronounced intra- and interindividual variability, which is, among other factors, related to smoking causing enzyme induction, to drug intake and to dietary factors which may result in induction or inhibition. In contrast to these exogenous factors, genetic influences on enzyme activity seem to be less pronounced. Therefore, phenotyping of CYP1A2, i.e. the determination of the actual activity of the enzyme in vivo, represents a useful approach both for scientific and clinical applications. CYP1A2 is almost exclusively expressed in the liver. Since liver tissue cannot be obtained for direct phenotyping, a probe drug which is metabolized by CYP1A2 has to be given. Proposed probe drugs include caffeine, theophylline, and melatonin. Caffeine is most often used because of the predominating role of CYP1A2 in its overall metabolism and the excellent tolerability. Various urinary, plasma, saliva, and breath based CYP1A2 caffeine metrics have been applied. While caffeine clearance is considered as the gold standard, the salivary or plasma ratio of paraxanthine to caffeine in a sample taken approximately 6 hr after a defined dose of caffeine is a more convenient, less expensive but also fully validated CYP1A2 phenotyping metric. CYP1A2 phenotyping is applied frequently in epidemiologic and drug-drug interaction studies, but its clinical use and usefulness remains to be established.

Journal Link  | PMID