Biochemistry- Xenobiotic Metabolism

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.

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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.

The role of genetic variability in drug metabolism pathways in breast cancer prognosis.

Choi, J-YN et al., 2006. Pharmacogenomics 7(4):613-624.

Abstract:

Among patients receiving adjuvant therapy for breast cancer, there is variability in treatment outcomes, and it is unclear which patients will receive the most benefit from treatment and which will have better disease-free survival. To date, most studies of breast cancer prognosis have focused on tumor characteristics, but it is likely that pharmacogenetics, genetic variability in the metabolism of therapeutic agents, also plays a role in the prediction of survival. In this paper, we briefly discuss the metabolic pathways of drugs commonly used for the treatment of breast cancer (cyclophosphamide, doxorubicin, taxanes, tamoxifen and aromatase inhibitors) and describe the known genetic variants that may impact those pathways. Studies that have evaluated potential effects of these genetic variants on treatment outcomes are also discussed. It is likely that the application of pharmacogenetics, particularly in the setting of randomized clinical trials, will contribute to findings that may result in individualized therapeutic dosing.

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Coffee, CYP1A2 genotype, and risk of myocardial infarction.

Cornelis, MC et al., 2006. J. Amer. Med. Assn. 295(10):1135-1141.

Abstract

Context The association between coffee intake and risk of myocardial infarction (MI) remains controversial. Coffee is a major source of caffeine, which is metabolized by the polymorphic cytochrome P450 1A2 (CYP1A2) enzyme. Individuals who are homozygous for the CYP1A2*1A allele are "rapid" caffeine metabolizers, whereas carriers of the variant CYP1A2*1F are "slow" caffeine metabolizers. Objective To determine whether CYP1A2 genotype modifies the association between coffee consumption and risk of acute nonfatal MI. Design, Setting, and Participants Cases (n = 2014) with a first acute nonfatal MI and population-based controls (n = 2014) living in Costa Rica between 1994 and 2004, matched for age, sex, and area of residence, were genotyped by restriction fragment-length polymorphism polymerase chain reaction. A food frequency questionnaire was used to assess the intake of caffeinated coffee. Main Outcome Measure Relative risk of nonfatal MI associated with coffee intake, calculated using unconditional logistic regression. Results Fifty-five percent of cases (n = 1114) and 54% of controls (n = 1082) were carriers of the slow *1F allele. For carriers of the slow *1F allele, the multivariate-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of nonfatal MI associated with consuming less than 1, 1, 2 to 3, and 4 or more cups of coffee per day were 1.00 (reference), 0.99 (0.69-1.44), 1.36 (1.01-1.83), and 1.64 (1.14-2.34), respectively. Corresponding ORs (95% CIs) for individuals with the rapid *1A/*1A genotype were 1.00, 0.75 (0.51-1.12), 0.78 (0.56-1.09), and 0.99 (0.66-1.48) (P = .04 for gene x coffee interaction). For individuals younger than the median age of 59 years, the ORs (95% CIs) associated with consuming less than 1, 1, 2 to 3, or 4 or more cups of coffee per day were 1.00, 1.24 (0.71-2.18), 1.67 (1.08-2.60), and 2.33 (1.39-3.89), respectively, among carriers of the *1F allele. The corresponding ORs (95% CIs) for those with the *1A/*1A genotype were 1.00, 0.48 (0.26-0.87), 0.57 (0.35-0.95), and 0.83 (0.46-1.51). Conclusion Intake of coffee was associated with an increased risk of nonfatal MI only among individuals with slow caffeine metabolism, suggesting that caffeine plays a role in this association.

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Comment

Coffee - a very practical example that faculty and students both can easily relate to in discussing possible interactions between genetic polymorphisms, dietary/environmental factors and disease risks.  it makes epidemiology a less abstract topic.  In addition, the data presented clearly demonstrate the relationship between genotype and diet (coffee consumption) and a patient's risk for myocardial infraction.

Genetic polymorphism of the adenosine A2A receptor is associated with habitual caffeine consumption.

Cornelis, MC et al., 2007. Am. J. Clin. Nutr. 86(1):240-244.

Abstract

BACKGROUND: Caffeine is the most widely consumed stimulant in the world, and individual differences in response to its stimulating effects may explain some of the variability in caffeine consumption within a population. OBJECTIVE: We examined whether genetic variability in caffeine metabolism [cytochrome P450 1A2 (CYP1A2) -163A-->C] or the main target of caffeine action in the nervous system [adenosine A(2A) receptor (ADORA2A) 1083C-->T] is associated with habitual caffeine consumption. DESIGN: Subjects (n=2735) were participants from a study of gene-diet interactions and risk of myocardial infarction who did not have a history of hypertension. Genotype frequencies were examined among persons who were categorized according to their self-reported daily caffeine intake, as assessed with a validated food-frequency questionnaire. RESULTS: The ADORA2A, but not the CYP1A2, genotype was associated with different amounts of caffeine intake. Compared with persons consuming <100 mg caffeine/d, the odds ratios for having the ADORA2A TT genotype were 0.74 (95% CI: 0.53, 1.03), 0.63 (95% CI: 0.48, 0.83), and 0.57 (95% CI: 0.42, 0.77) for those consuming 100-200, >200-400, and >400 mg caffeine/d, respectively. The association was more pronounced among current smokers than among nonsmokers (P for interaction = 0.07). Persons with the ADORA2A TT genotype also were significantly more likely to consume less caffeine (ie, <100 mg/d) than were carriers of the C allele [P=0.011 (nonsmokers), P=0.008 (smokers)]. CONCLUSION: Our findings show that the probability of having the ADORA2A 1083TT genotype decreases as habitual caffeine consumption increases. This observation provides a biologic basis for caffeine consumption behavior and suggests that persons with this genotype may be less vulnerable to caffeine dependence.

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Comment

As with the above citation, this more recent paper by Cornelis addresses coffee consumption, but the focus is on an 'addiction' to coffee.  Using the now standard combination of population biology and genomics approaches the authors demonstrate a correlation be coffee addiction and the adenosine A(2A) receptor gene which is expressed in the nervous system.  Interestingly, the Cyp1A2 gene appears to not be involved with the addiction tendency though it is critical in the metabolism of the caffeine in coffee.

Clinical significance of the cytochrome P450 2C19 genetic polymorphism.

Desta, Z et al., 2002. Clin Pharmacokinet 41(12):913-58.

Abstract

Cytochrome P450 2C19 (CYP2C19) is the main (or partial) cause for large differences in the pharmacokinetics of a number of clinically important drugs. On the basis of their ability to metabolise (S)-mephenytoin or other CYP2C19 substrates, individuals can be classified as extensive metabolisers (EMs) or poor metabolisers (PMs). Eight variant alleles (CYP2C19*2 to CYP2C19*8) that predict PMs have been identified. The distribution of EM and PM genotypes and phenotypes shows wide interethnic differences. Nongenetic factors such as enzyme inhibition and induction, old age and liver cirrhosis can also modulate CYP2C19 activity. In EMs, approximately 80% of doses of the proton pump inhibitors (PPIs) omeprazole, lansoprazole and pantoprazole seem to be cleared by CYP2C19, whereas CYP3A is more important in PMs. Five-fold higher exposure to these drugs is observed in PMs than in EMs of CYP2C19, and further increases occur during inhibition of CYP3A-catalysed alternative metabolic pathways in PMs. As a result, PMs of CYP2C19 experience more effective acid suppression and better healing of duodenal and gastric ulcers during treatment with omeprazole and lansoprazole compared with EMs. The pharmacoeconomic value of CYP2C19 genotyping remains unclear. Our calculations suggest that genotyping for CYP2C19 could save approximately 5000 US dollars for every 100 Asians tested, but none for Caucasian patients. Nevertheless, genotyping for the common alleles of CYP2C19 before initiating PPIs for the treatment of reflux disease and H. pylori infection is a cost effective tool to determine appropriate duration of treatment and dosage regimens. Altered CYP2C19 activity does not seem to increase the risk for adverse drug reactions/interactions of PPIs. Phenytoin plasma concentrations and toxicity have been shown to increase in patients taking inhibitors of CYP2C19 or who have variant alleles and, because of its narrow therapeutic range, genotyping of CYP2C19 in addition to CYP2C9 may be needed to optimise the dosage of phenytoin. Increased risk of toxicity of tricyclic antidepressants is likely in patients whose CYP2C19 and/or CYP2D6 activities are diminished. CYP2C19 is a major enzyme in proguanil activation to cycloguanil, but there are no clinical data that suggest that PMs of CYP2C19 are at a greater risk for failure of malaria prophylaxis or treatment. Diazepam clearance is clearly diminished in PMs or when inhibitors of CYP2C19 are coprescribed, but the clinical consequences are generally minimal. Finally, many studies have attempted to identify relationships between CYP2C19 genotype and phenotype and susceptibility to xenobiotic-induced disease, but none of these are compelling.

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Cytochrome P450 isoforms, drug interactions, and inhibitors.

Flockhart, DA, 2005. Website at http://medicine.iupui.edu/flockhart/

Abstract

This table is designed as a hypothesis testing, teaching and reference tool for physicians and researchers interested in drug interactions that are the result of competition for, or effects on the human cytochrome P450 system. Clinicians and health care providers may find an abbreviated clinical table designed for practical use during prescribing more useful. The table contains lists of drugs in columns under the designation of specific cytochrome P450 isoforms. A drug appears in a column if there is published evidence that it is metabolized, at least in part, via that isoform. It does not necessarily follow that the isoform is the principal metabolic pathway in vivo, or that alterations in the rate of the metabolic reaction catalyzed by that isoform will have large effects on the pharmacokinetics of the drug.

Comment

This is an excellent site to access a detailed Cytochrome P450 Drug-Interaction Table.  This table lists interactions between the major Cytochrome P450 enzymes and their substrates and various inhibitors, substances which will induce over-expression from their respective Cyp genes, and some population genetics of the polymorphic forms of these enzymes.  Many of these table entries are hotlink to other information resources.

Codeine intoxication associated with ultrarapid CYP2D6 metabolism.

Gasche, Y et al., 2004. N. Engl. J. Med. 351(27):2827-2831.

Life-threatening opioid intoxication developed in a patient after he was given small doses of codeine for the treatment of a cough associated with bilateral pneumonia. Codeine is bioactivated by CYP2D6 into morphine, which then undergoes further glucuronidation. CYP2D6 genotyping showed that the patient had three or more functional alleles, a finding consistent with ultrarapid metabolism of codeine. We attribute the toxicity to this genotype, in combination with inhibition of CYP3A4 activity by other medications and a transient reduction in renal function

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Comment

An excellent review of codeine drug therapy and the normal metabolism of codeine to its inactive excreted form vs. its active morphine metabolite, and the roles of gene polymorphisms of cytochrome P450 enzymes on these processes.  The paper includes an excellent illustration that could serve as a model for lecture presentation figures.

Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose.

Rieder, M et al., 2005. N. Engl. J. Med. 352(22):2285-2293.

Abstract

BACKGROUND: The management of warfarin therapy is complicated by a wide variation among patients in drug response. Variants in the gene encoding vitamin K epoxide reductase complex 1 (VKORC1) may affect the response to warfarin. METHODS: We conducted a retrospective study of European-American patients receiving long-term warfarin maintenance therapy. Multiple linear-regression analysis was used to determine the effect of VKORC1 haplotypes on the warfarin dose. We determined VKORC1 haplotype frequencies in African-American, European-American, and Asian-American populations and VKORC1 messenger RNA (mRNA) expression in human liver samples. RESULTS: We identified 10 common noncoding VKORC1 single-nucleotide polymorphisms and inferred five major haplotypes. We identified a low-dose haplotype group (A) and a high-dose haplotype group (B). The mean (+/-SE) maintenance dose of warfarin differed significantly among the three haplotype group combinations, at 2.7+/-0.2 mg per day for A/A, 4.9+/-0.2 mg per day for A/B, and 6.2+/-0.3 mg per day for B/B (P<0.001). VKORC1 haplotype groups A and B explained approximately 25 percent of the variance in dose. Asian Americans had a higher proportion of group A haplotypes and African Americans a higher proportion of group B haplotypes. VKORC1 mRNA levels varied according to the haplotype combination. CONCLUSIONS: VKORC1 haplotypes can be used to stratify patients into low-, intermediate-, and high-dose warfarin groups and may explain differences in dose requirements among patients of different ancestries. The molecular mechanism of this warfarin dose response appears to be regulated at the transcriptional level.

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Association of pharmacokinetic (CYP2C9) and pharmacodynamic (factors II, VII, IX, and X; proteins S and C; and ?-glutamyl carboxylase) gene variants with warfarin sensitivity.

Shikata, E et al., 2004.  Blood 103(7):2630-2635

We analyzed mutations of 7 vitamin K--dependent protein and cytochrome P450 2C9 genes in 45 patients and investigated whether any contribute to the large interpatient variability in the warfarin dose-effect relationship. Total clearance and daily dose, INR and INR/Cp, were used as pharmacokinetic and pharmacodynamic indexes, respectively. Patients were grouped by genotype based on a single polymorphism and combinations of polymorphisms. Among the 30 sequence variants identified, CYP2C9*3, 165Thr --> Met of the factor II gene, -402G --> A, (37-bp repeat)n, and -746T --> C of the factor VII gene, and (CAA repeat)n of the ?-glutamyl carboxylase gene were selected as candidate polymorphisms. As the analysis of single polymorphisms implied, the highest INR/Cp mean values and the lowest warfarin maintenance doses were observed in patients homozygous for the 165Met, -402G, (37-bp repeat)6 and -746T alleles. Multiple regression analysis revealed that warfarin sensitivity was independently associated with -402G --> A, (CAA repeat)n, CYP2C9*3, and 165Thr --> Met, which accounted for 50% of variance. These results suggest that part of the considerable interpatient variation is attributable to genetic variation, and the combined genotyping of CYP2C9 and certain vitamin K--dependent protein genes is useful for predicting anticoagulant responses.

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Comment

One advantage of this research paper is its discussion of the various different gene products involved in blood coagulation.  It lays out how several different genes can each be polymorphic, producing individual enzymes with varying degrees of activity.  Thus, how one responds to a fixed dose of warfarin depends on one's constellation of enzymes that metabolize warfarin and those that recycle the oxidized/reduced forms of vitamin K.

Pharmacogenetics of warfarin: current status and future challenges.

Wadelius, M. &Pirmohamed, M, 2006. Pharmacogenomics J. 7(2):99-111.

Abstract

Warfarin is an anticoagulant that is difficult to use because of the wide variation in dose required to achieve a therapeutic effect, and the risk of serious bleeding. Warfarin acts by interfering with the recycling of vitamin K in the liver, which leads to reduced activation of several clotting factors. Thirty genes that may be involved in the biotransformation and mode of action of warfarin are discussed in this review. The most important genes affecting the pharmacokinetic and pharmacodynamic parameters of warfarin are CYP2C9 (cytochrome P(450) 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1). These two genes, together with environmental factors, partly explain the interindividual variation in warfarin dose requirements. Large ongoing studies of genes involved in the actions of warfarin, together with prospective assessment of environmental factors, will undoubtedly increase the capacity to accurately predict warfarin dose. Implementation of pre-prescription genotyping and individualized warfarin therapy represents an opportunity to minimize the risk of haemorrhage without compromising effectiveness.

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