M/S dosage recommendations of antidepressants for multiple-dosing or for beginning of treatment in relation to CYP2D6 and CYP2C19 polymorphism (M-maintenance treatment, S-single dose) (Kirchheiner et al., 2001).
1. Introduction
Pharmacogenetics (or pharmacogenomics) studies the role of inherited and acquired genetic variation in drug response. Clinically relevant pharmacogenetic examples, mainly involving drug metabolism are known for decades, but the field was not evolved until the 1970s, when the discovery of the CYP2D6 polymorphism and its resultant effect on drug toxicity and response led to many observations of pharmacogenetic-based variations in pharmacokinetics. These and other discoveries and the subsequent ability to genotype led to the term pharmacogenetics. Today, as a consequence of sequencing and mapping of the human genome, pharmacogenetics is becoming the first drug discovery pipeline technology to affect the structure and economics of the pharmaceutical industry (Daly, 2010). During drug development, it is important to consider pharmacogenetic variation which could explain or even prevent discarding a drug candidate if appropriate genetic reasons are identified or when lack of response/occurrence of ADRs (adverse drug reactions) in drug therapy is experienced. Genetic variation is taken strongly into consideration also in clinic during individualized therapies. It helps to improve the number of responders and decrease the number of patients suffering from ADRs.
Beside genetic polymorphism there are other heritable phenotypic changes which play role in drug response that do not involve any alteration in nuclear DNA sequence, but affect gene transcription through DNA methylation, histone modification, miRNA regulation (called pharmacoepigenetic changes) (Berger et al., 2009). There are also non-heritable changes, which affect response to drugs, such as reactions to the environment, to drug-drug interactions through regulatory mechanisms (Tamási et al., 2003). Although fast, non-heritable responses, which alter signal transduction pathways affect the therapeutic outcome of a drug tremendously, pharmacogenetic and pharmacoepigenetic difference has to be taken also strictly into consideration in clinical practice.
In general one can envision important pharmacogenetic and pharmacoepigenetic variation
in genes responsible for pharmacokinetic properties of the drug (genes influencing absorption, distribution metabolism, elimination) or
in genes responsible for pharmacodinamic properties of the drug (genes affecting the pharmacologic effect of a drug) (Daly, 2010).
So far, it is apparent that heritable changes in genes encoding drug metabolizing enzymes often affects outcome in drug treatment to a high degree and the variability of the phase I enzymes plays major role in this respect, as evidenced by many studies (Spear et al., 2001; Ingelman-Sundberg, 2004a; Weinshilboum, 2003). In general it can be estimated that 20-25% of all drug therapies are influenced by such polymorphism to an extent that therapy outcome is changed. There are much fewer examples where the pharmacodinamic properties are influenced and it has clinical relevance (Ingelman-Sundberg, 2004b; Eichelbaum et al., 2006).
In this book chapter the polymorphic and epigenetic nature of phase I enzymes will be discussed and their role in therapy and clinic will be highlighted.
2. Pharmacogenetics
All genes encoding cytochrome P450 enzymes (CYPs) in families 1–3 are polymorphic. However, the functional importance of the variant alleles is not the same and the frequency of their distribution in different ethnic groups also differs. Polymorphisms of CYPs consist of single nucleotide polymorphisms (SNP), gene deletions, missense mutations, insertions, gene duplications and deleterious mutations creating inactive gene products. Furthermore amino acid changes might be introduced, which changes the substrate specificity of the enzyme. Mutations in intronic regions could also have relevance. An important aspect of drug metabolizing gene polymorphism would be copy number variation (CNV) where multiple functional gene copies of one allele can result in increased drug metabolism and absence of drug response at ordinary dosage. To order and standardize allelic variants, the CYP-allele nomenclature committee manages the naming and definition of CYP alleles, which are presented on an associated web site (http://www.cypalleles.ki.se). The homepage contains updated information regarding the nomenclature and properties of the variant alleles with links to the dbSNP database (http://www.ncbi.nlm.nih.gov/projects/SNP/) and relevant literature references. Based on the phenotype variability among drug metabolizers, the populations could be classified into four major groups:
the ultrarapid metabolizers (UM); with very high drug metabolizing capacity; usually caring more than two active gene copies
the extensive metabolizers (EM); with high drug metabolizing capacity; usually caring two active gene copies
the intermediate metabolizers (IM); with intermediate drug metabolizing capacity; usually carrying one functional and one defective allel, but may also carry two partially defective alleles
the poor metabolizers (PM); with slow, poor drug metabolizing capacity; usually lacking functional enzyme due to defective or deleted genes (Ingelman-Sundberg et al., 2007).
Taking CYP2D6-dependent metabolism as an example, the rate of metabolism for a certain drug can differ 1000-fold between phenotypes. Thus, the dosing required to achieve the same plasma levels of a drug metabolized mainly by CYP2D6, such as nortriptyline, differs 10–20-fold among individuals. Despite this extensive variation in metabolic capacity among patients, dosing is, at present, principally population based (i.e. doses are based on the plasma levels of the drug obtained on average in the population at a certain dosage), but not individual based.
CYP polymorphisms affect the response of individuals to drugs in many ways (see Fig 1.) and it alters the therapial regimen of many diseases such as depression, psychosis, cancer, cardiovascular disorders, ulcer and gastrointestinal disorders, pain and epilepsy and many others. The problem is that the use of genotyping or genomic methods to inform clinical decisions about drug response are not widely practiced (Varmus, 2010) but it would be necessary, expecially when drugs have narrow therapeutic indexes, when severe side effects occur or when the rate of non-responders is high. In resent years, the FDA has aggressively pursued drug-label modification when excess risk can be convincingly linked to a genetic marker. The FDA-mandated incorporation of pharmacogenomic information in drug labeling will remain an important step in the acceptance of pharmacogenomics in clinical practice (Wolf & Smith, 2000).
In the next section, relevant therapeutic areas where CYP polymorphism significantly influences the response of drugs or the incidence of adverse drug reactions will be presented.
2.1. Role of pharmacogenetics in therapies
At the present time, decisions about which medications to prescribe are made on a trial and error basis for many disorders. Under the pharmacogenomic paradigm, genetically based screening methods would allow the tailoring of drug therapy, drug selection and dosing according to an individual's ability to metabolize a drug. There are many disorders where it is already taken into consideration and applying information about the patient's genetic makeup has high impact on therapeutic outcome.
2.1.1. Cancer
Oncology is a field that is already being revolutionized by pharmacogenomics. Cancer pharmacogenomics is complicated by the fact that two genomes ar involved: the germline genome of the patient and the somatic genome of the tumor. Chemotherapeutic drugs are very sensitive to genetic background, since in general they are unspecific drugs with narrow therapeutic indexes that result frequent severe or even fatal toxicities.
Another CYP enzyme, CYP2C19 has been shown to metabolize tamoxifen to its active form. Carriers of CYP2C19*17 allele variants have been shown to exhibit a more favourable clinical outcome, since these patients activate tamoxifen in greater extent. This allele may be especially relevant for patients with low levels of CYP2D6 (Rodriguez-Antona et al., 2010).
CYP3A4 tumor expression could be somatically altered in specific tumors and it could be useful predictor for the effectiveness of drugs that are subject to CYP3A4 metabolism (for e.g. drug resistance in cancer tissue). Vincristine, CPA, etoposide treatments in lymphoma or docetaxel in breast cancer are all substrates of tumor CYP3A4 and their local metabolism could have therapeutical consequences due to their narrow therapeutical window. CYP2B1 is also overexpressed in breast cancer and there are several therapeutic approaches focusing on higher CYP2B1 metabolism in tumor cells than in other body cells (Rodriguez-Antona et al., 2010).
2.1.2. Depression
CYP2D6 and CYP2C19 metabolize virtually all of the antidepressants, many of which are also strong inhibitors of the enzyme.
Tricyclic antidepressants (TCAs) are medications used to alleviate mood disorders, such as major depression dysthymia or anxiety disorders. CYP2D6 mediated metabolism of antidepressants leads to equally potent metabolites but the risk for side effects in poor metabolizers for CYP2D6 has been shown to be higher than in extensive metabolizers even if the sum of parent drug and metabolite was the same. Because of these adverse effects, in case of TCAs, there should be a dose adjustment depending on the patients genotype (for e.g. single dose paroxetine is changing 10-fold in EMs compared to PMs) (Table 1.). Genotyping for
Drug | Dosing | Usual dose (mg) | EM (%) | IM (%) | PM (%) |
CYP2D6-dependent | |||||
Amitriptyline | M | 150 | 120 | 90 | 50 |
S | 50 | 120 | 80 | 70 | |
Nortriptyline | M | 150 | 120 | 90 | 50 |
S | 50 | 140 | 70 | 50 | |
Imipramine | M | 150 | 130 | 80 | 30 |
S | 50 | 110 | 100 | 60 | |
Paroxetine | M | 20 | 110 | 90 | 70 |
S | 20 | 130 | 70 | 20 | |
Venlafaxine | M | 150 | 130 | 80 | 20 |
CYP2C19-dependent | |||||
Amitryptiline | M | 150 | 110 | 80 | 60 |
Imipramine | M | 150 | 100 | 80 | 60 |
S | 50 | 100 | 90 | 70 | |
Clomipramine | S | 50 | 100 | 90 | 70 |
CYP2C19 polymorphism also influences the blood level of citalopram, amitriptyline and other antidepressants (Table 1.). Amitriptyline is demethylated to nortriptyline by CYP2C19 which is further metabolised to nonactive metabolites. CYP2C19 polymorphism alone does not affect the therapeutic outcome, since nortriptyline the metabolite is an active antidepressant, but side effects are different if the amitriptyline/nortriptilline balance is changing. The highest risk for ADRs occur when a patient is EM for CYP2C19, but PM for CYP2D6, since CYP2C19 produces a high amount of nortriptyline, but there is no CYP2D6 to metabolize it to inactive metabolites (Jornil et al., 2010).
The pharmacokinetics of serotonin reuptake inhibitors (SSRIs) is complex, they are very lipid solible, high clearence drugs subjected to multiple metabolic pathways.
2.1.3. Psychosis
Antipsychotic drugs are widely prescribed for a multitude of psychiatric conditions. CYP2D6 metabolizes many psychotropic drugs, including antipsychotics like haloperidol, thioridazine, perphenazine, chlorpromazine, risperidone, and aripiprazole.
Numerous authors suggested that genotyping for families of CYP enzymes (CYP2D6, CYP1A2) could potentially aid in prescribing antipsychotic drugs, since there are significant risks associated with their polymorphism, such as movement disorders (CYP1A2, CYP2D6), and cardiovascular adverse effects (CYP2D6) (Foster et al., 2007). CYP2D6 PMs had four time higher Parkinsonism like side-effects than EMs. Also, occurence of other ADRs in response to treatment increased from CYP2D6 EMs to PMs. Furtermore, the duration of treatment was higher in PM patients, which increased the costs about 4000-6000$ (Ingelman Sundberg, 2004b).
2.1.4. Epilepsy
Effective dosing of phenytoin is highly linked to CYP2C9 genotype. Patient cariing defective alleles show more frequently side effects for e.g. ataxia, diploidia and other neurological symptoms (Lee et al., 2002). Clobazam is also used in the treatment of epilepsy. This drug is metabolized to N-demethylclobazam, which is further processed by CYP2C19 to 4-hydroxydesmethylclobazam. In CYP2C19 PM patients there is an accumulation of N-demethylclobazam, which causes side effects such as drowsiness (Kosaki et al., 2004). Diazepam, another antiepileptic and anxiolitic is metabolized by CYP2C19 and CYP3A4. Both enzymes convert it to desmethyldiazepam. CYP2C19 produces two other metabolites also, oxazepam and temazepam (Andersson et al., 1994; Jung et al., 1997). PMs for CYP2C19 enzyme metabolize slower this drug and took longer to emerge from anesthesia than for EMs (Inomata et al., 2005). Although diazepam has a clear gene-concentration effect, it is not predictable for the dose because of the many other active metabolites produced and involvement of other CYP enzymes.
2.1.5. Pain
Gasche et al reported a patient who received oral codeine at daily dose of 75 mg and who experienced symptoms of morphine overdose (lack of consciusness, respiratory depression) after 4 days of treatment. The patient recovered after intravenous administration of naloxon. The cause of these sympthomes was his CYP2D6 EM phenotype as genotyping showed 3 or more functional alleles. The patient was concomitatantly treated with claritromycin and voriconazole, both known inhibitors of CYP3A4 as confirmed by low CYP3A4 activity (Gasche et al., 2004)
Effects of metabolised codeine | EM | PM |
Morphine conc. (% of codeine) | 3.9% | 0.17% |
Analgesia | Yes | No |
Pricking pain threshold | Increased | No effect |
Tolerance thresholds to heat and pressure | Not altered | Not altered |
Peak pain and disconfort during cold pressor test | Reduced | Not changed |
Adverse effects | Yes | Yes |
2.1.6. Cardiovascular diseases
Genetic variation influences the dose of many cardiovascular drugs, because most of them has narrow therapeutic indexes. Cardiovascular diseases are treated with many different classes of drugs, such as antianginals, antihypertensives, antiarrhythmics, anticoagulants, antiaggregating agents, lipid lowering drugs, etc. Many of these drugs are metabolized through the polymorphic CYP2D6, CYP2C9 and CYP2C19 enzymes.
For example, the antianginal perhexiline metabolism is controlled by the polymorphic CYP2D6 enzyme. After perhexiline treatment a gene-dose effect has been observed; in poor metabolizers, perhexiline plasma concentrations can be very high (6-fold higher than in EMs after a single dose of perhexiline) which explains its hepatotoxic and neuropathic side effects. Determination of the ratio between perhexiline and its metabolite early in treatment may facilitate appropriate dose adjustment which may range from 10 mg in PMs to 500 mg in EMs (Cooper et al., 1984).
CYP2C9 and the C1 subunit of the vitamin K epoxide reductase (VKORC1) genotypes are associated with the variability in the overall pharmacodynamic responses to oral anticoagulants, such as warfarin, acenocoumarol and phenprocoumon. All three molecules have low therapeutic indexes and the dose required to produce a normal prothrombin time is largely unpredictable. The consequences of under or over treating can be dire (thromboembolism or hemorrhage) (Gardiner & Begg, 2006).
Gene | Allele | Outcome |
VKORC1 | 3673;G-1639A | GG (insensitive), GA (sensitive), AA (most sensitive) |
GGCX | C"/>G | CC (less sensitve), CG (more sensitive), GG (most sensitive) |
CALU | 11G"/>A;R4Q | GG (less sensitive), GA (more sensitive), AA (most sensitive) |
CYP4F2 | C"/>T; V433M | CC (most sensitive), CT (more sensitive),TT (less sensitive) |
CYP2C9 | CYP2C9*2 ;R144C CYP2C9*3 ;I359L CYP2C9*5 CYP2C9*6 | CC (*1/*1, wild type), CT (*1/*2, IM), TT (*2/*2, PM) AA (wild type), AC (-/*3, PM), CC(*3/*3, PM) CC (wild type), CG (-/*5, PM), GG (*5/*5, PM) AA (wild type), A-(-/*6, PM), --(*6/*6, PM) |
Two common CYP2C9 allozymes have only a fraction of the level of enzyme activity of the wild type allozyme CYP2C9*1: 12% for CYP2C9*2 and 5% for CYP2C9*3. Since VKORC1, CALU and GGCX genotype together with CYP2C9 and CYP4F2 genotype and factors such as age, body size may account just for 50-60% of the variability in warfarin dosing requirements, prothrombin time monitoring is still necessary during dose adjustment. But still, genotypization is recommended because of risk of side effects caused by the pharmacodinamic properties of warfarin (strong gene-dose relationship, strong dose-effect relationship and low therapeutic index). In 2010 the FDA revised the label on warfarin providing genotype-specific ranges of doses and suggesting that genotypes should be taken into consideration when the drug is prescribed (Wang et al., 2011; Takahashi et al., 1998).
Absorption of clopidogrel in the gut is opposed by the efflux pump P-glycoprotein, encoded by the
Antiarrhythmia drugs are used to treat abnormal heart rhythms resulting from irregular electrical activity of the heart. Most antiarrhythmics are metabolized via CYP3A or CYP2D6 (Gardner et al., 2006).
Beta-blockers reduce the effects of the sympathetic nervous system on the cardiovascular system. These drugs are effective against high blood pressure, congestive heart failure, abnormal heart rhythms or chest pain. Their pharmacokinetic is very diverse; those which are metabolised by polymorph CYP enzymes are carvedilol, metoprolol, propranolol and timolol.
CYP2C9 metabolizes several antihypertensive angiotensin II receptor antagonists, such as losartan, irbesartan, candesartan or valsartan. Although losartan and candesartan are activated, irbesartan is metabolised by CYP2C9, there is no need for genotyping of the enzyme variants during the treatment (Gardiner et al., 2006).
2.1.7. Metabolic disorders
CYP2C9 is the main enzyme catalyzing the biotransformation of sulphanylureas such as tolbutamide, glyburine, glimeprimide and glipizide. The total oral clearence of sulphanylureas has been shown to be 20% in PM persons of that in wild type, whereas the clearence in heterozygous carriers was between 50% and 80% of that of wild type genotype. Therefore, adverse effects of many oral antidiabetics may be reduced by CYP2C9 genotype-based dose adjustments (Gardiner et al., 2006).
2.1.8. Gastrointestinal disorders
The PPIs undergo extensive hepatic biotransformation by the CYP system. The principal isoenzymes involved in the metabolism of the PPIs are CYP2C19 and CYP3A4 (Andersson et al., 1998; Pierce et al., 1996). CYP2C19 is the main enzyme involved in the metabolism of PPIs omeprazole, pantoprazole and lansoprazole and the CYP2C19 genotype is a strong determinant of the acid inhibitory effect of these drugs. Higher doses of the PPIs should be used in homozygous EMs (e.g. 40 mg), and lower doses could be used in heterozygous EMs and PMs (e.g. 10 mg).
Eradication therapy | Eradication rate (%) | Av. cure rate (%) | |||
EM | IM | PM | |||
Dual therapy | Omeprazole/Amoxicillin 20 mg 1x/500mg/two weeks 4x daily | 30 | 60 | 100 | 63 |
Omeprazole/Amoxicillin 40 mg 1x/2000mg/one week 4x daily | 33 | 30 | 100 | 54 | |
Rabeprazole/Amoxicillin 10 mg 2x/500mg/two weeks 3x daily | 60 | 92,2 | 92 | 80 | |
Triple therapy | Omeprazole/Amoxicillin/Clarithromycin 40 mg 1x/1500mg/600 mg/one week 4x daily | 81 | 94,5 | 100 | 92 |
Genotyping is also important in Helicobacter pylori eradication (Table 4.). If patients are confirmed as being PMs, dual therapy with PPI plus amoxicillin may be appropriate, as the eradication rate is likely to be high (>90%). This regimen has the advantage of being cheaper and less complex than triple therapy regimens. Individuals identified as homozygous EMs might be better to commence a triple drug regimen (PPI, amoxicillin and clarithromycin).
2.1.9. Infection
2.1.10. Rheumatoid arthritis
Nonsteroid antiinflamatory drugs (NSAID) are commonly used for rheumatoid arthritis treatment and many of them are metabolised by the CYP2C9 enzyme. The low activity alleles of CYP2C9 (CYP2C9*2, CYP2C9*3) has been shown to influence the pharmacokinetics of ibuprofen, naproxen, diclofenac and celecoxib (Kircheiner & Brockmoller, 2005). From these drugs, celexocib and ibuprofen have extensive CYP2C9 metabolism (Kircheiner et al., 2002; Lundblad et al., 2006). In PM patients for CYP2C9 these two drugs have 2-7 fold longer effects and stronger gastrointestinal side effects (Martin et al., 2001).
3. Pharmacoepigenetics
Much of the interindividual variation in drug response has been addressed by pharmacogenetics and it is imperative for clinicians to consider during determination drug efficacy and reducing side effects. But it is important to note that many inherited and acquired discrepancies cannot be resolved only by sequencing the whole genome and identifying genetic variations, there are other heritable factors affecting the activity of a gene such as covalent modification of DNA and histones, DNA packaging around nucleosomes, chromatin folding and attachment to the nuclear matrix or miRNA regulation. These changes together are called epigenetic changes and with true genetics they show how genes might interact with their surroundings to produce a phenotype. It means that beside genetic information, epigenetic factors have to be also taken into consideration during determinating variation in drug response. Beside individual variations, there could be a pharmacoepigenetic basis for other drug related effects, such as drug resistance (for e.g. doxorubicin resistance due to epigenetic regulation of ABCG2 transporter in cancer cells) (Calgano et al., 2008).
In the following section, an overview has been provided of new results in the field related to regulation by DNA methylation, histone modulation and miRNA, since they are topics of considerable current interest which may describe the large variation in expression seen for several important CYPs (Okino et al., 2006; Antilla et al., 2003; Dannenberg et al., 2006; Tamási et al., 2011).
3.1. Epigenetic regulation
The modified histones, methylated DNA sequences and miRNAs may interact in a synergistic manner, including methyl-CpG binding protein, nuclear receptor corepressor (NCoR), associated histone deacetylases, histone methyl transferases and epi-miRNAs to regulate gene expression (Yoon et al., 2003). The mentioned epigenetic changes affect the expression of drug metabolizing enzymes and with that ultimately affect the pharmacokinetic or pharmacodinamic properties of a drug.
3.2. Epigenetic regulation of P450s
Both hypermethylation (less active CYP1A1, slower metabolism of drugs) and hypomethylation (more active enzyme, higher metabolic rate) of CYP1A1 is described, mostly in cancer tissue. In prostate cells, CpG islands in CYP1A1 show segmented/selective methylation patterns: CpG sites from 1 to 36 are not methylated; this DNA region contains the
Chromatin structure has been suggested to play an essential role in
miRNA regulation of CYP1A1 is also known. miRNA regulation by miRNA-18b and miRNA-20b of CYP1A1 was described by Wang and coworkers and a significant correlation was found between the mentioned miRNAs and CYP1A1 expression (Wang et al., 2009).
Methylation | Histon modification | miRNA | ||||
CpG region | Compound/ disease | Modification | Compound/ disease | miRNA | Tissue/ cell | |
CYP1A1 | Enchancer/ promoter | Cancer, tobacco smoke | Acetylation | B[a]P | Hsa-miR-18b, Hsa-miR-20b | Transformed lymphocytes |
CYP1B1 | Enchancer/ promoter | Cancer | - | - | Hsa-miR-27b | Cancer |
Hsa-miR-124 | Brain | |||||
CYP2E1 | Region not described | Ethanol | - | - | Hsa-miR-378 | HEK293 |
CYP2W1 | I.exon/ I.intron | Cancer | - | - | - | - |
CYP3A | Enchancer/ promoter | Cancer | Methylation | Rifampicin | Hsa-miR-27b | HEK293 |
Hsa-miR-148a | Liver |
Human CYP1B1, which is highly expressed in estrogen target tissues, catalyzes the 4-hydroxylation of 17-beta-estradiol. Tsuchiya and coworkers found an abundant amount of CYP1B1 protein in breast cancerous tissue and they identified a near-perfect matching sequence with miR-27b in the 3’-untranslated region of human CYP1B1. Human CYP1B1 is post-transcriptionally regulated by miR-27b (Tsuchya et al., 2006). Another brain-specific miRNA, miR-124, also downregulates CYP1B1 directly and modulate all AHR target genes indirectly by binding to AHR receptor (Lim et al., 2005).
Mohri and coworkers recently found that miR-378 is involved in the post-transcriptional regulation of CYP2E1. The overexpression of miR-378 significantly decreased CYP2E1 protein levels and enzyme activity in the cells expressing CYP2E1, including 3’-UTR, but not in the cells expressing CYP2E1 without 3’-UTR, indicating that the 3’-UTR plays a role in the miR-378-dependent repression (Mohri et al., 2010). Chronically induced CYP2E1 with ethanol or other CYP2E1 inducers is a high-risk factor for esophageal and gastrointestinal cancers, which gives importance to investigate transcriptional and post-transcriptional CYP2E1 regulatory mechanisms, as basic targets in anticancer therapy.
Different DNA methylation pattern was found between primary hepatocytes and hepatocyte cell lines. HepG2 cells exhibit many cellular features of normal human hepatocytes, but also display characteristics resembling those of a cancerous or fetal hepatocyte.
CYP3A4 transcription is also regulated by a histone methyltransferase enzyme called protein arginine methyltransferase 1 (PRMT1). PRMT1 is required for the transcriptional activity of CYP3A4 by pregnane X receptor (PXR). It is recruited to 5'-region of the CYP3A4 gene to methylate histone H4 as a response to the PXR agonist rifampicin (Xie et al., 2009). CYP3A4 is also regulated by constitutive androstane receptor (CAR) albeit it at a lower rate of expression. Assenat and coworkers reported that the synthetic glucocorticoid, dexamethasone, induces histone H4 acetylation at the proximal CAR promoter region, and indirectly affects CYP3A4 induction by regulating CAR expression (Assenat et al., 2004).
Until now, one miRNA, miR-27b, has been described to regulate CYP3A4 expression by binding to the miRNA response element (MRE) within the 3’UTR region of CYP3A4 mRNA (Pan et al., 2009). Some miRNAs, such as miR-148a, which is selectively and abundantly expressed in the liver, regulates other liver specific genes, for e.g., the human PXR. miR-148a binds to the 3’-UTR region of PXR mRNA, thereby decreasing synthesis of PXR protein. Since CYP3A4 is a target for PXR, miR-148a indirectly modulates the inducible and/or constitutive levels of CYP3A4 expression (Takagi et al., 2008). Another example of indirect modulation would be the vitamine D receptor (VDR). VDR also regulates CYP3A4 and VDR could be down-regulated with miR-27b (Mohri et al., 2010).
4. Conclusion
Pharmacogenetics and pharmacoepigenetics is a scientific field which understands the role of an individual’s genetic background in how well a medicine works, and also what side effects occur during drug administration. The development of pharmacogenetics/ pharmacoepigenetics (for benefits and limitations see Fig 2.) provides at least one mechanism for taking prescription away from its current empiricism and progressing towards more “individualised” drug treatment.
The clinical applicability of pharmacogenetic testing depends on the relative importance of each polymorphism in determining therapeutic outcome. Doctors need to be aware of whether a drug they are prescribing is subject to pharmacogenetic variability and they have to know how to use this knowledge. Routine genotyping or phenotyping before drug administration can be made for very few drugs today and we are still a long way from having a pharmacogenetic DNA chip that general practitioners can use to identify all the drugs to which any particular patient is sensitive. There are many issues against testing, including specific factors that contaminate the signal, such as active metabolites/enantiomers, access and availability of the tests, complication for patients etc.
What have been changed as a result of pharmacogenetic knowledge until today is the drug-label modifications. There are more and more drug-labels where the pharmacogenetic consequence is highlighted (Table 6.). Drug labels may contain information on genomic biomarkers and can describe: drug exposure and clinical response variability, risk for adverse events, genotype-specific dosing, mechanisms of drug action, polymorphic drug target, disposition genes etc.
CYP enzymes | FDA-approved drugs with pharmacogenomic information in their labels |
CYP2C9 | Clopidogrel, Diazepam, Dextansoprazole, Drospirenone and Ethenyl Estradiol, Esomeprazole, Nelfinavir, Rabeprazole, Voriconazole |
CYP2C19 | Celexocib, Warfarin |
CYP2D6 | Aripiprazole, Atomoxetine, Carvedilol, Cevimeline, Clozapine, Codeine, Dextromethorphan and Quinidine, Doxepin, Fluoxetine, Fluoxetine and Olanzapine, Metoprolol, Propafenone, Propranolol, Protryptiline, Quinidine, Risperidone, Terbinafine, Tetrabenazine, Thioridazine, Timolol, Tiotropium, Tolterodine, Tramadol and Acetaminophen,Venlafaxine |
Another result of pharmacogenetic knowledge is including pharmacogenomics into clinical trials. Carlquist and Anderson reported that this year until May, a total of 158 pharmacogenomic clinical trials were listed at http://www.clinicaltrials.gov. Of those trials the three leading disease areas for which pharmacogenetic guided intervention is sought were cancer (37%), psychiatric disorders (13%), and anticoagulation/thrombosis (9%) (Carlquist & Anderson, 2011).
In addition to pharmacogenetics, it has been also predicted that DNA methylation, histone modification and RNA-mediated regulation also affects gene expression. Until now, cancer is the only disease, where pharmacoepigenetics of drug metabolizing enzymes seems to be important. Epigenetic changes influence sensitivity to chemotherapeutic drugs suggesting that epigenetic factors could serve as molecular markers predicting the responsiveness of tumors and other diseases to therapy.
Ultimately, it could be concluded that pharmacogenetics and pharmacoepigenetics explains in large extent individual variation of drug metabolising enzymes and hopefully these two factors together will help to work out more specific dosing protocols for drugs.
References
- 1.
Andersson T. Holmberg J. Rohss K. Walan A. 1998 Pharmacokinetics and effect on caffeine metabolism of the proton pump inhibitors, omeprazole, lansoprazole, and pantoprazole. ,45 369 375 ,0306-5251 - 2.
Andersson T. Miners J. O. Veronese M. E. Birkett D. J. 1994 Diazepam metabolism by human liver microsomes is mediated by both S-mephenytoin hydroxylase and CYP3A isoforms. ,38 131 137 ,0306-5251 - 3.
Anttila S. Hakkola J. Tuominen P. Elovaara E. Husgafvel-Pursiainen K. Karjalainen A. Hirvonen A. Nurminen T. 2003 Methylation of cytochrome P4501A1 promoter in the lung is associated with tobacco smoking. 63 8623 8628 ,0008-5472 - 4.
Aoyama N. Tanigawara Y. Kita T. Sakai T. Shirakawa K. Shirasaka D. Kodama F. Okumura K. Kasuga M. 1999 Sufficient effect of 1-week omeprazole and amoxicillin dual treatment for Helicobacter pylori eradication in cytochrome P450 2C19 poor metabolizers. ,34 80 83 ,0944-1174 - 5.
Assenat E. Gerbal-Chaloin S. Larrey D. Saric J. Fabre J. M. Maurel P. Vilarem M. J. Pascussi J. M. 2004 Interleukin 1beta inhibits CAR-induced expression of hepatic genes involved in drug and bilirubin clearance.40 4 951 960 ,0169-5185 - 6.
Berger S. L. Kouzarides T. Shiekhattar R. Shilatifard A. 2009 An operational definition of epigenetics.23 7 781 783 ,0890-9369 - 7.
Bloomer J. C. Woods F. R. Haddock R. E. Lennard M. S. Tucker G. T. 1992 The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes.33 521 523 ,0306-5251 - 8.
Botto F. Seree E. el Khyari S. de Sousa G. Massacrier A. Placidi M. Cau P. Pellet W. Rahmani R. Barra Y. 1994 Tissue-specific expression and methylation of the human CYP2E1 gene. 48 6 1095 1103 ,0006-2952 - 9.
Calcagno A. M. Fostel J. M. To K. K. Salcido C. D. Martin S. E. Chewning K. J. Wu C. P. Varticovski L. Bates S. E. Caplen N. J. Ambudkar S. V. 2008 Single-step doxorubicin-selected cancer cells overexpress the ABCG2 drug transporter through epigenetic changes.98 9 1515 1524 ,0007-0920 - 10.
Carlquist J. F. Anderson J. L. 2011 Pharmacogenetic mechanisms underlying unanticipated drug responses.11 60 469 478 ,1539-6509 - 11.
Cooper R. G. Evans D. A. P. Whibley E. J. 1984 Polymorphic hydroxylation of perhexiline maleate in man.21 27 33 ,0022-2593 - 12.
Daly A. K. 2010 Pharmacogenetics and human genetic polymorphisms.429 3 435 449 ,0264-6021 - 13.
Dannenberg L. O. Edenberg H. J. 2006 Epigenetics of gene expression in human hepatoma cells: expression profiling the response to inhibition of DNA methylation and histone deacetylation.19 7 181 1471-2164 - 14.
Daigo S. Takahashi Y. Fujieda M. Ariyoshi N. Yamazaki H. Koizumi W. Tanabe S. Saigenji K. Nagayama S. Ikeda K. Nishioka Y. Kamataki T. 2002 A novel mutant allele of the CYP2A6 gene (CYP2A6*11 ) found in a cancer patient who showed poor metabolic phenotype towards tegafur. Pharmacogenetics,12 299 306 ,0096-0314 X - 15.
De Smet C. Lurquin C. Lethe B. Martelange V. Boon T. 1999 DNA methylation is the primary silencing mechanism for a set of germ line- and tumor-specific genes with a CpG-rich promoter.19 11 7327 7335 ,0270-7306 - 16.
Edler D. Stenstedt K. Ohrling K. Hallstrom M. Karlgren M. Ingelman-Sundberg M. Ragnhammar P. 2009 The expression of the novel CYP2W1 enzyme is an independent prognostic factor in colorectal cancer- a pilot study.45 4 705 712 ,0014-2964 - 17.
Eichelbaum M. Ingelman-Sundberg M. Evans W. E. 2006 Pharmacogenomics and individualized drug therapy.57 119 137 ,0066-4219 - 18.
Foster A. Wang Z. Usman M. Stirewalt E. Buckley P. 2007 Pharmacogenetics of antipsychotic adverse effects: Case studies and a literature review for clinicians.3 6 965 973 ,1176-6328 - 19.
Fulco P. P. Zingone M. M. Higginson R. T. 2008 Possible antiretroviral therapy-warfarin drug interaction.28 7 945 949 ,0277-0008 - 20.
Fuller R. W. Snoddy H. D. Krushinski J. H. Robertson D. W. 1992 Comparison of norfluoxetine enantiomers as serotonin uptake inhibitors in vivo. ,31 997 1000 ,0028-3908 - 21.
Furuta T. Shirai N. Sugimoto M. Nakamura A. Hishida A. Ishizaki T. 2005 Influence of CYP2C19 pharmacogenetic polymorphism on proton pump inhibitor-based therapies.20 3 153 167 ,1347-4367 - 22.
Futscher B. W. Oshiro M. M. Wozniak R. J. Holtan N. Hanigan C. L. Duan H. Domann F. E. 2002 Role for DNA methylation in the control of cell type specific maspin expression. 31 175 179 ,1061-4036 - 23.
Gardiner S. J. Begg E. J. 2006 Pharmacogenetics, drug-metabolizing enzymes, and clinical practice.58 3 521 590 ,0031-6997 - 24.
Gasche Y. Daali Y. Fathi M. Chiappe A. Cottini S. Dayer P. Desmeules J. 2004 Codeine intoxication associated with ultrarapid CYP2D6 metabolism.351 2827 2831 ,0028-4793 - 25.
Ghanayem B. I. Hoffler U. 2007 Investigation of xenobiotics metrabolism, genotoxicity and carcinogenicity using cyp2e1(-/-) mice.8 728 749 ,1389-2002 - 26.
Gomez A. Karlgren M. Edler D. Bernal M. L. Mkrtchian S. Ingelman-Sundberg M. 2007 Expression of CYP2W1 in colon tumors: regulation by gene methylation.8 10 1315 1325 ,1462-2416 - 27.
Hirani V. N. Raucy J. L. Lasker J. M. 2004 Conversion of the HIV protease inhibitor nelfinavir to a bioactive metabolite by human liver CYP2C19.32 12 1462 1467 ,0090-9556 - 28.
Ingelman-Sundberg M. 2004a Human drug metabolising cytochrome P450 enzymes: properties and polymorphisms.369 89 104 ,0003-9780 - 29.
Ingelman-Sundberg M. 2004b Pharmacogenetics of cytochrome P450 and its applications in drug therapy: the past, present and future.25 4 193 200 ,0165-6147 - 30.
Ingelman-Sundberg M. Sim S. C. Gomez A. Rodriguez-Antona C. 2007 Influence of cytochrome P450 polymorphisms on drug therapies: pharmacogenetic, pharmacoepigenetic and clinical aspects.116 3 496 526 ,0362-5486 - 31.
Inomata S. Nagashima A. Itagaki F. Homma M. Nishimura M. Osaka Y. Okuyama K. Tanaka E. Nakamura T. Kohda Y. Naito S. Miyabe M. Toyooka H. 2005 CYP2C19 genotype affects diazepam pharmacokinetics and emergence from general anesthesia.78 647 655 ,0009-9236 - 32.
Jenuwein T. Allis C. D. 2001 Translating the histone code.293 1074 1080 ,0193-3396 - 33.
Jin Y. Desta Z. Stearns V. Ward B. Ho H. . Lee K. H. Skaar T. Storniolo A. M. Li L. Araba A. Blanchard R. Nguyen A. Ullmer L. Hayden J. Lemler S. Weinshilboum R. M. Rae J. M. Hayes D. F. Flockhart D. A. 2005 CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst,97 30 39 ,1052-6773 - 34.
Jornil J. Jensen K. G. Larsen F. Linnet K. 2010 Identification of cytochrome P450 isoforms involved in the metabolism of paroxetine and estimation of their importance for human paroxetine metabolism using a population-based simulator. ,38 3 376 385 ,0090-9556 - 35.
Jung F. Richardson T. H. Raucy R. L. Johnson E. F. 1997 Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P450 2C19 as low KM diazepam N-demethylases. ,25 133 139 ,0090-9556 - 36.
Karlgren M. Ingelman-Sundberg M. 2007 Tumour-specific expression of CYP2W1: its potential as a drug target in cancer therapy.11 1 61 67 ,1472-8222 - 37.
Kellermann G. Shaw C. R. Luyten-Kellermann M. 1973 Aryl hydrocarbon hydroxylase inducibility and bronchogenic carcinoma.289 934 937 ,0028-4793 - 38.
Kirchheiner J. Meineke I. Freytag G. Meisel C. Roots I. Brockmoller J. 2002 Enantiospecific effects of cytochrome P450 2C9 amino acid variants on ibuprofen pharmacokinetics and on the inhibition of cyclooxygenase 1 and 2. ,72 62 75 ,0009-9236 - 39.
Kircheiner J. Brockmoller J. 2005 Clinical consequences of cytochrome P450 polymorphisms.77 1 16 ,0009-9236 - 40.
Kirchheiner J. Brøsen K. Dahl M. L. Gram L. F. Kasper S. Roots I. Sjöqvist F. Spina E. Brockmöller J. 2001 CYP2D6 and CYP2C19 genotype-based dose recommendations for antidepressants: a first step towards subpopulation-specific dosages.104 3 173 192 ,0000-1690 X - 41.
Kirchheiner J. Nickchen K. Bauer M. Wong M. L. Licinio J. Roots I. Brockmöller J. 2004 Pharmacogenetics of antidepressants and antipsychotics: the contribution of allelic variations to the phenotype of drug response.9 5 442 473 ,1359-4184 - 42.
Kosaki K. Tamura K. Sato R. Samejima H. Tanigawara Y. Takahashi T. 2004 A major influence of CYP2C19 genotype on the steady-state concentration of N-desmethylclobazam.26 530 534 ,0387-7604 - 43.
Kouzarides T. 2007 Chromatin modifications and their function.128 693 705 ,0092-8674 - 44.
Kroemer H. K. Funck-Brentano C. Silberstein D. J. Wood A. J. J. Eichelbaum M. Woosley R. L. Roden D. M. 1989a Stereoselective disposition and pharmacologic activity of propafenone enantiomers.79 1068 1076 ,0009-7322 - 45.
Kroemer H. K. Mikus G. Kronbach T. Meyer U. A. Eichelbaum M. 1989b In vitro characterization of the human cytochrome P-450 involved in polymorphic oxidation of propafenone.45 28 33 .0009-9236 - 46.
Labbe L. Turgeon J. 1999 Clinical pharmacokinetics of mexiletine.37 361 384 ,0312-5963 - 47.
Laine K. Tybring G. Hartter S. Andersson K. Svensson J. O. Widen J. Bertilsson L. 2001 Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test.70 327 335 ,0009-9236 - 48.
Lee C. R. Goldstein J. A. Pieper J. A. 2002 Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data.12 3 251 263 ,0096-0314 X - 49.
Lennard M. S. Jackson P. R. Freestone S. Ramsay L. E. Tucker G. T. Woods H. F. 1984 The oral clearance and ß-adrenoceptor antagonist activity of propranolol after single dose are not related to debrisoquine oxidation phenotype.17 106S 107S ,0306-5251 - 50.
Leppert W. 2011 CYP2D6 in the Metabolism of Opioids for Mild to Moderate Pain.87 5-6 ,274 285 ,0031-7012 - 51.
Li W. Tang Y. Hoshino T. Neya S. 2009 Molecular modeling of human cytochrome P450 2W1 and its interactions with substrates.28 2 170 176 ,1093-3263 - 52.
Lim L. P. Lau N. C. Garrett-Engele P. Grimson A. Schelter J. M. Castle J. Bartel D. P. Linsley P. S. Johnson J. M. 2005 Title microarray analysis shows that some microRNAs down regulate large numbers of target mRNAs.433 7027 769 773 ,0028-0836 - 53.
Lundblad M. S. Ohlsson S. Johansson P. Lafolie P. Eliasson E. 2006 Accumulation of celecoxib with a 7-fold higher drug exposure in individuals homozygous for CYP2C9*3.79 287 288 ,0009-9236 - 54.
Margolis J. M. O’Donnell J. P. Mankowski D. C. Ekins S. Obach R. S. 2000 (R)-, (S)-, and racemic fluoxetine N-demethylation by human cytochrome P450 enzymes.28 1187 1191 ,0090-9556 - 55.
Martin J. H. Begg E. J. Kennedy M. A. Roberts R. Barclay M. L. 2001 Is cytochrome P450 2C9 genotype associated with NSAID gastric ulceration?51 627 630 ,0306-5251 - 56.
Mc Fadyen M. C. Breeman S. Payne S. Stirk C. Miller I. D. Melvin W. T. Murray G. I. 1999 Immunohistochemical localization of cytochrome P450 CYP1B1 in breast cancer with monoclonal antibodies specific for CYP1B1.47 1457 1464 ,0022-1554 - 57.
Mc Gourty J. C. Silas J. H. Fleming J. J. Mc Burney A. Ward J. W. 1985b Pharmacokinetics and ß-blocking effects of timolol in poor and extensive metabolizers of debrisoquin.38 409 413 ,0009-9236 - 58.
Mc Gourty J. C. Silas J. H. Lennard M. S. Tucker G. T. Woods H. F. 1985a Metoprolol metabolism and debrisoquine metabolism-population and family studies.20 555 566 ,0306-5251 - 59.
Mikus G. Gross A. S. Beckmann J. Hertrampf R. Gundert-Remy U. Eichelbaum M. 1989 The influence of the sparteine/debrisoquin phenotype on the disposition of flecainide.45 562 567 ,0009-9236 - 60.
Mohri T. Nakajima M. Fukami T. Takamiya M. Aoki Y. Yokoi T. 2010 Human CYP2E1 is regulated by miR-378.79 7 1045 1052 ,0006-2952 - 61.
Murray G. I. Taylor M. C. Mc Fadyen M. C. Mc Kay M. C. J. A. Greenlee W. F. Burke M. D. Melvin W. T. 1997 Tumor-specific expression of cytochrome P450 CYP1B1.57 3026 3031 ,0008-5472 - 62.
Niemi M. Backman J. T. Fromm M. F. Neuvonen P. J. Kivistö K. T. 2003 Pharmacokinetic interactions with rifampicin : clinical relevance.42 9 819 850 ,0312-5963 - 63.
Okino S. T. Pookot D. Li L. C. Zhao H. Urakami S. Shiina H. Dahiya R. 2006 Epigenetic inactivation of the dioxin-responsive cytochrome P4501A1 gene in human prostate cancer.66 7420 7428 ,0008-5472 - 64.
Oldham H. G. Clarke S. E. 1997 In vitro identification of the human cytochrome P450 enzymes involved in the metabolism of R(_)- and S(_)-carvedilol.25 970 977 ,0090-9556 - 65.
Pan Y. Z. Gao W. Yu A. M. 2009 MicroRNAs regulate CYP3A4 expression via direct, indirect targeting.37 10 2112 2117 ,0090-9556 - 66.
Pearce R. E. Rodrigues A. D. Goldstein J. A. Parkinson A. 1996 Identification of the human P450 enzymes involved in lansoprazole metabolism.277 805 816 ,0022-3565 - 67.
Rodriguez-Antona C. Gomez A. Karlgren M. Sim S. C. Ingelman-Sundberg M. 2010 Molecular genetics and epigenetics of the cytochrome P450 gene family and its relevance for cancer risk and treatment.127 1 1 17 ,0340-6717 - 68.
Rotger M. Colombo S. Furrer H. Bleiber G. Buclin T. Lee B. L. Keiser O. Biollaz J. Decosterd L. A. Telenti A. 2005 Influence of CYP2B6 polymorphism on plasma and intracellular concentrations and toxicity of efavirenz and nevirapine in HIV infected patients.15 1 5 .1744-6872 - 69.
Rountree M. R. Bachman K. E. Herman J. G. Baylin S. B. 2001 DNA methylation, chromatin inheritance and cancer.20 3156 3165 ,0950-9232 - 70.
Schnekenburger M. Peng L. Puga A. 2007 HDAC1 bound to the Cyp1a1 promoter blocks histone acetylation associated with Ah receptor-mediated trans-activation.1769 9-10 ,569 578 ,0006-3002 - 71.
Simon T. Verstuyft C. Mary-Krause M. Quteineh L. Drouet E. Méneveau N. Steg P. G. Ferrières J. Danchin N. Becquemont L. 2009 French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events.360 4 363 375 ,0028-4793 - 72.
Siddoway L. A. Thompson K. A. Mc Allister C. B. Wang T. Wilkinson G. R. Roden D. M. Woosley R. L. 1987 Polymorphism of propafenone metabolism and disposition in man: clinical and pharmacokinetic consequences.75 785 791 ,0009-7322 - 73.
Song F. Smith J. F. Kimura M. T. Morrow A. D. Matsuyama T. Nagase H. Held W. A. 2005 Association of tissue-specific differentially methylated regions (TDMs) with differential gene expression. ,102 3336 3341 ,0027-8424 - 74.
Spear B. B. Heath-Chiozzi M. Huff J. 2001 Clinical application of pharmacogenetics.7 201 204 ,1471-4914 - 75.
Spreafico M. Peyvandi F. Pizzotti D. Moia M. Mannucci P. M. 2002 Warfarin and acenocoumarol dose requirements according to CYP2C9 genotyping in North- Italian patients.1 2252 2253 ,1538-7933 - 76.
Stein R. Razin A. Cedar H. 1982 In vitro methylation of the hamster adenine phosphoribosyltransferase gene inhibits its expression in mouse L cells.79 3418 3422 ,0027-8424 - 77.
Stücker I. Jacquet M. de Waziers I. Cénée S. Beaune P. Kremers P. Hémon D. 2000 Relation between inducibility of CYP1A1, GSTM1 and lung cancer in a French population.10 617 627 ,0096-0314 X - 78.
Takada K. Arefayene M. Desta Z. Yarboro C. H. Boumpas D. T. Balow J. E. Flockhart D. A. Illei G. G. 2004 Cytochrome P450 pharmacogenetics as a predictor of toxicity and clinical response to pulse cyclophosphamide in lupus nephritis. Arthritis Rheum,50 2202 2210 ,0004-3591 - 79.
Takahashi H. Kashima T. Nomoto S. Iwade K. Tainaka H. Shimizu T. Nomizo Y. Muramoto N. Kimura S. Echizen H. 1998 Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes.8 365 373 ,0096-0314 X - 80.
Takagi S. Nakajima M. Mohri T. Yokoi T. 2008 Post-transcriptional regulation of human pregnane X receptor by micro- RNA affects the expression of cytochrome P450 3A4.283 15 9674 9680 ,0021-9258 - 81.
Tamási V. Monostory K. Prough R. A. Falus A. 2011 Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s.68 7 1131 1146 ,0142-0682 X - 82.
Tamási V. Vereczkey L. Falus A. Monostory K. 2003 Some aspects of interindividual variations in the metabolism of xenobiotics.52 8 322 333 ,1023-3830 - 83.
Tanigawara Y. Aoyama N. Kita T. Shirakawa K. Komada F. Kasuga M. Okumura K. 1999 CYP2C19 genotype-related efficacy of omeprazole for the treatment of infection called by Helicobacter pylori.66 528 534 ,0009-9236 - 84.
Tate P. H. Bird A. P. 1993 Effects of DNA methylation on DNA-binding proteins and gene expression.3 226 231 ,0095-9437 X - 85.
Tokizane T. Shiina H. Igawa M. Enokida H. Urakami S. Kawakami T. Ogishima T. Okino S. T. Li L. C. Tanaka Y. Nonomura N. Okuyama A. Dahiya R. 2005 Cytochrome P450 1B1 is overexpressed and regulated by hypomethylation in prostate cancer.11 5793 5801 ,1078-0432 - 86.
Toon S. Heimark L. D. Trager W. F. O’Reilly R. A. 1985 Metabolic fate of phenprocoumon in humans.74 1037 1040 ,0022-3549 - 87.
Tsuchiya Y. Nakajima M. Takagi S. Taniya T. Yokoi T. 2006 MicroRNA regulates the expression of human cytochrome P450 1B1.66 18 9090 9098 ,0008-5472 - 88.
Vangsted A. J. Søeby K. Klausen T. W. Abildgaard N. Andersen N. F. Gimsing P. Gregersen H. Vogel U. Werge T. Rasmussen H. B. 2010 No influence of the polymorphisms CYP2C19 and CYP2D6 on the efficacy of cyclophosphamide, thalidomide, and bortezomib in patients with Multiple Myeloma.4 10 40 44 ,1471-2407 - 89.
Varmus H. 2010 Ten years on--the human genome and medicine.362 21 2028 2029 ,0028-4793 - 90.
Vieira I. Pasanen M. Raunio H. Cresteil T. 1998 Expression of CYP2E1 in human lung and kidney during development and in full-term placenta: a differential methylation of the gene is involved in the regulation process.83 5 183 187 ,0901-9928 - 91.
Vieira I. Sonnier M. Cresteil T. 1996 Developmental expression of CYP2E1 in the human liver. Hypermethylation control of gene expression during the neonatal period.238 2 476 483 ,0014-2956 - 92.
Wang L. Mc Leod H. L. Weinshilboum R. M. 2011 Genomics and drug response.364 12 1144 1153 ,0028-4793 - 93.
Wang L. Oberg A. L. Asmann Y. W. Sicotte H. Mc Donnell S. K. Riska S. M. Liu W. Steer C. J. Subramanian S. Cunningham J. M. Cerhan J. R. Thibodeau S. N. 2009 Genome-wide transcriptional profiling reveals microRNA-correlated genes and biological processes in human lymphoblastoid cell lines.4 6 e. 5878,1932-6203 - 94.
Weber M. Hellmann I. Stadler M. B. Ramos L. Paabo S. Rebhan M. Schubeler D. 2007 Distribution, silencing potential and evolutionary impact of promoter DNA methylation in the human genome.39 457 466 ,1061-4036 - 95.
Weinshilboum R. 2003 Inheritance and drug response.348 529 537 ,0028-4793 - 96.
Wolf C. R. Smith G. 1999 Pharmacogenetics.55 2 366 386 ,0007-1420 - 97.
Xie Y. Ke S. Ouyang N. He J. Xie W. Bedford M. T. Tian Y. 2009 Epigenetic regulation of transcriptional activity of pregnane X receptor by protein arginine methyltransferase 1.284 14 9199 9205 ,0021-9258 - 98.
Yoon H. G. Chan D. W. Reynolds A. B. Qin J. Wong J. 2003 N-CoR mediates DNA methylation-dependent repression through a methyl CpG binding protein Kaiso.12 723 734 ,1097-2765