Cytochrome P CYP enzymes are essential for the production of cholesterol, steroids, prostacyclins, and thromboxane A 2. They also are necessary for the detoxification of foreign chemicals and the metabolism of drugs. CYP enzymes are so named because they are bound to membranes within a cell cyto and contain a heme pigment chrome and P that absorbs light at a wavelength of nm when exposed to carbon monoxide. One out of every 15 white or black persons may have an exaggerated response to standard doses of beta blockers e.
This is because drug metabolism via CYP enzymes exhibits genetic variability polymorphism that influences a patient's response to a particular drug. A specific gene encodes each CYP enzyme.
Every person inherits one genetic allele from each parent. Polymorphism occurs when a variant allele replaces one or both wild-type alleles. Variant alleles usually encode a CYP enzyme that has reduced or no activity. Finally, some persons inherit multiple copies of wild-type alleles, which results in excess enzyme activity. CYP enzyme polymorphism is responsible for observed variations in drug response among patients of differing ethnic origins.
Genotype testing may predict persons who are poor metabolizers or are nonresponsive to drugs metabolized by CYP enzymes. Large, prospective trials needed to demonstrate that genotype testing improves outcomes and is cost-effective. Genetic variations in CYP metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses.
Patients should be monitored closely for the development of adverse drug effects or therapeutic failures when a potent CYP enzyme inhibitor or inducer is added to drugs metabolized by one or more CYP enzymes. Severe toxicity can result if CYP enzyme—inhibiting drugs are added to the following medications: atypical antipsychotics, benzodiazepines, cyclosporine Sandimmune , statins, or warfarin Coumadin.
Particularly true if substrate drug depends on only one CYP enzyme for metabolism. Because they are known to cause clinically significant CYP drug interactions, always use caution when adding the following substances to medications that patients are taking: amiodarone Cordarone , antiepileptic drugs, antidepressants, antitubercular drugs, grapefruit juice, macrolide and ketolide antibiotics, nondihydropine calcium channel blockers, or protease inhibitors.
Many drug interactions are the result of an alteration of CYP metabolism. Drugs interact with the CYP system in several ways. Drugs may be metabolized by only one CYP enzyme e. Inhibitors block the metabolic activity of one or more CYP enzymes. The extent to which an inhibitor affects the metabolism of a drug depends upon factors such as the dose and the ability of the inhibitor to bind to the enzyme.
For instance, sertraline Zoloft is considered a mild inhibitor of CYP2D6 at a dose of 50 mg, but if the dose is increased to mg, it becomes a potent inhibitor. Amiodarone, cimetidine, diphenhydramine Benadryl , fluoxetine, paroxetine Paxil , quinidine, ritonavir, terbinafine Lamisil. Amitriptyline, carvedilol, codeine, donepezil Aricept , haloperidol Haldol , metoprolol Lopressor , paroxetine, risperidone Risperdal , tramadol Ultram.
Carbamazepine, Hypericum perforatum St. John's wort , phenobarbital, phenytoin, rifampin. Alprazolam Xanax , amlodipine Norvasc , atorvastatin Lipitor , cyclosporine Sandimmune , diazepam Valium , estradiol Estrace , simvastatin Zocor , sildenafil Viagra , verapamil, zolpidem Ambien.
Information from references 10 and 14 through Additionally, a drug can be both metabolized by and inhibit the same enzyme e. Ritonavir Norvir , a protease inhibitor and potent CYP3A4 inhibitor, is added to lopinavir Kaletra to boost serum levels in patients with human immunodeficiency virus.
Inducers increase CYP enzyme activity by increasing enzyme synthesis. Unlike metabolic inhibition, there is usually a delay before enzyme activity increases, depending on the half-life of the inducing drug. A decrease in the concentration of a drug metabolized by CYP2C9 can occur within 24 hours after the initiation of rifampin Rifadin , an inducer with a short half-life, but can occur up to one week after the initiation of phenobarbital, an inducer with a very long half-life.
Carbamazepine Tegretol , a potent enzyme inducer, must be initiated at a low dose and then increased at weekly intervals as its half-life gradually decreases over time. The following clinical scenario describes a case of drug interaction: A year-old white woman taking warfarin, whose condition was previously well controlled on a stable dose, has recently been difficult to anticoagulate to a therapeutic level.
Review of her medications reveals the addition of monthly fluconazole Diflucan for recurrent vulvo-vaginal candidiasis.
The physician recognizes the drug interaction between warfarin and fluconazole as a potential cause and switches the patient to an alternate antifungal agent. The patient's International Normalized Ratio quickly stabilizes.
As shown in this example, physicians should be cautious when prescribing a drug known to be a CYP inhibitor or inducer. The target drug may need to be substituted or the dose adjusted to account for a potential decrease or increase in metabolism. Information regarding a drug's CYP metabolism and its potential for inhibition or induction can be found on the drug label and accessed through the U. The FDA has required this information for every drug approved since Table 2 19 — 28 lists examples of common drug-drug interactions and their potential clinical effects.
Table 3 14 , 16 lists some useful CYP drug interaction resources. Increased risk of bleeding caused by increased warfarin level Unplanned pregnancy caused by reduced estradiol level Myopathy or rhabdomyolysis caused by increased simvastatin level Hypotension and QT interval prolongation caused by increased verapamil level Immunosuppression caused by increased prednisolone serum levels Increased risk of extrapyramidal adverse effects caused by increased risperidone level 24 ; decrease in analgesic effect caused by low level of active metabolite Dizziness and serotonin syndrome caused by increased buspirone level Dry mouth, dizziness, and cardiac toxicity caused by prolonged increase in amitriptyline and nortriptyline Pamelor levels Information from references 19 through Comprehensive guide to drug interactions with useful charts and representative cases.
Continually updated table of important substrates, inhibitors, and inducers with direct links from each drug name to a PubMed list of citations. This PDA software includes a section on cytochrome P enzyme activity for each drug narrative. Information from reference 14 and Standard drug doses may cause adverse effects related to elevated drug serum levels if a person is a poor metabolizer or has a CYP enzyme inhibitor added to therapy. Consider the following scenario: A year-old white woman with panic disorder was treated with paroxetine Paxil.
She developed unrelated hypertension, for which the physician prescribed 50 mg daily of extended-release metoprolol Toprol XL. The patient became symptomatically orthostatic after a few days and presented to the emergency department. In this example, metoprolol, which is metabolized solely by CYP2D6, was present in higher serum levels in the patient because of the use of paroxetine. The polymorphisms can result in defective or increased enzyme activity and CYP2D6 genotypes usually exhibit large inter-ethnic differences.
By contrast, the role of CYP2D6 in the metabolism of precarcinogens is minor and the polymorphism of the enzyme is apparently without importance for interindividual differences in susceptibility for cancer. CYP2D6 has been shown to play a crucial role in the metabolism of tamoxifen, which is an estrogen receptor modulator widely used for the endocrine treatment of all stages of hormone receptor-positive breast cancer.
Tamoxifen is activated by the CYP system to antioestrogenic metabolites that are more potent than the parent compound Jin et al. In patients receiving tamoxifen, the most abundant compounds in plasma are N -desmethyltamoxifen and endoxifen, and it has been shown that endoxifen has approximately times greater affinity for the oestrogen receptor than tamoxifen and N -desmethyltamoxifen Jordan et al.
Thus, in a study of 80 women with breast cancer starting tamoxifen adjuvant therapy, the plasma concentrations of endoxifen after 4 months of therapy were significantly lower in patients being homozygous or heterozygous for defective CYP2D6 genes as compared to those with two functional alleles Jin et al.
The CYP2D6 genotype is also relevant for cancer patients with respect to the action of the antiemetic drugs tropisetron and ondasetron.
Lower plasma levels and higher frequency and intensity of vomiting were found in subjects carrying a higher number of active CYP2D6 gene copies Kaiser et al. Chemical structure of tamoxifen and major biotransformation pathways. The most abundant compounds in plasma are N -desmethyltamoxifen and endoxifen, and endoxifen has approximately times greater affinity for the oestrogen receptor than tamoxifen and N -desmethyltamoxifen.
CYP2D6 polymorphisms have been shown to affect the plasma concentrations of endofixen. CYP2E1 is responsible for the metabolism and activation of a large number of low-molecular-weight chemicals, solvents, cancer suspect agents and a few drugs Table 2.
Thus, CYP2E1 might be an important determinant of human susceptibility to toxicity and carcinogenicity of industrial and environmental chemicals.
However, polymorphisms affecting CYP2E1 expression or activity have not been found, probably because of high conservation due to a critical role of the enzyme in gluconeogenesis during conditions of starvation. By contrast, induction of the enzyme by, for example, alcohol might provide a more important factor for interindividual susceptibility to cancer in reactions mediated by CYP2E1. The expression of these enzymes is regulated in a tissue-specific manner, the P s being predominant in the liver and gastrointestinal tract.
Interindividual variation in CYP3A activity, thus, has a major impact on pharmacokinetics and metabolism of a majority of different drugs. This variation can be caused by environmental factors or drugs that inhibit or induce CYP3A enzymes but, additionally, it has been shown that the variation is determined to a high extent by genetic factors Ozdemir et al.
However, this is not true for CYP3A4 since, despite the analysis of thousands of subjects, no major functionally variant allele has been found at an allele frequency higher than 0.
The basis for any genetic background for the interindividual variation in CYP3A4 expression remains a challenge. With respect to the action of anticancer drugs, the variability of CYP3A4 is expected to influence the outcome of several different treatments. Docetaxel is metabolized by CYP3A4 to inactive hydroxylated derivatives Figure 3 and, therefore, a high CYP3A4 activity would result in a poor therapeutic outcome of the drug.
Similarly, hepatic CYP3A4 activity measured by the erythromycin breath test and midazolam clearance predicted docetaxel clearance, finding the greatest toxicity in patients with the lowest CYP3A4 activity Hirth et al. Furthermore, Yamamoto et al.
In addition, CYP3A4 expression in breast tumour tissue has been shown to predict therapeutic response to docetaxel Miyoshi et al.
Similarly to docetaxel, irinotecan is inactivated by CYP3A4 and induction of CYP3A4 in patients receiving irinotecan results in a significant decrease in the formation of the toxic metabolite of this drug Friedman et al. Additionally, Mathijssen et al. Table 3 also shows other important anticancer agents metabolized by CYP3A4, including taxanes, vinca-alkaloids and new drugs such as imatinib and gefitinib.
Chemical structure of docetaxel and major biotransformation pathways. In addition to an interindividual variability in the pharmacokinetics of anticancer drugs caused by hepatic CYPs, an altered CYP activity in the tumour cells could result in an altered drug efficacy. Cancer cells by means of genetic or epigenetic mechanisms, due to their higher DNA instability and more frequent alterations in chromatin structure than nontumour cells, could alter P transcription.
The capacity of the tumours to metabolize drugs is a potential means to achieve optimal therapy by activation of prodrugs in the cancer cells; however, it is also a potential mechanism of resistance to therapy by an increased inactivation of anticancer drugs caused by an overexpression of P s.
Many studies have reported the presence of drug-metabolizing enzymes in tumours Dhaini et al. However, differences in the quantification and sampling techniques and heterogeneous patient populations have resulted, in some cases, in conflicting data, making it difficult to conclude about any impact on deactivation of anticancer agents or activation of prodrugs.
With respect to the impact of tumour P s on drug therapy outcome, Tanaka et al. In all, 12 genes with proven functional significance to drug sensitivity, which included CYP2C8 and CYP3A4 , were selected and prediction models to accurately predict the in vitro efficacy of the drugs were developed. The in vivo relevance of the model was tested for 5-fluorouracil treatment in gastric cancer patients. The model of predictive value in terms of survival, time to treatment failure and tumour growth showed that the tumour phenotype was indeed related to the therapeutic response to 5-fluorouracil Tanaka et al.
Miyoshi et al. Similarly, Dhaini et al. CYP3A4 is involved in the oxidation of compounds that are usually used as chemotherapeutic agents for the treatment of osteosarcomas such as etoposide, ifosfamide, cyclophosphamide and doxorubicin, suggesting that the response to these drugs could be worse in tumours with high CYP3A expression, increasing the risk of metastasis. Therefore, the main hepatic drug metabolizing P enzymes if expressed in the tumour cells could influence the success of drug therapy.
In addition, some extrahepatic P s, many of which have major roles in the metabolism of endogenous substrates and are not involved in xenobiotic biotransformation, have been found to be overexpressed in tumour tissue. CYP2J2 is able to metabolize arachidonic acid to epoxyeicosatrienoic acids, which have been suggested to play a role in angiogenesis and to exert antiapoptotic effects Chen et al.
CYP2J2 was much overexpressed relative to adjacent normal tissue in the majority of tumours examined, which included esophageal squamous cell carcinoma, esophageal adenocarcinoma, pulmonary squamous cell carcinoma, pulmonary adenocarcinoma, small-cell pulmonary carcinoma, breast carcinoma, stomach carcinoma, liver carcinoma and colon adenocarcinoma Jiang et al.
CYP2W1 has been shown to be almost exclusively expressed during embryogenesis and in adult humans it is mainly detected in tumour tissue samples, more frequently from colon and adrenal gland Karlgren et al.
With respect to CYP4Z1, it is regulated by the glucocorticoid and progesterone receptors and has been shown to be overexpressed preferentially in breast carcinoma tissue and mammary gland Rieger et al. A major objective of cancer research is the development of therapeutic agents specifically targeted to tumour cells.
P s expressed at higher levels in the tumour cells than in the surrounding normal tissue offer therapeutic options by the activation of prodrugs specifically in the cancer cells and avoiding undesirable systemic effects see Riddick et al. In this respect, there are therapeutic options and opportunities arising from both the enhanced endogenous expression of CYP in tumours and CYP-mediated gene therapy.
Concerning endogenous overexpression of individual forms of P enzymes in tumour cells, CYP1B1 is the best studied example, because although several CYP1As, CYP2Cs and CYP3As exhibit enhanced expression in some tumour cells, these enzymes display considerable expression in normal tissue, mainly in the liver.
Taking advantage of this, several agents activated by CYP1B1 are currently in preclinical evaluation, such as resveratrol and phortress Potter et al. The polymorphism of these genes in relation to the success of P based cancer therapy remains to be elucidated.
The enzyme expression can be genetically controlled or its delivery targeted to ensure tumour selectivity. The gene-directed enzyme prodrug therapy systems with CYP have been mainly based on cyclophosphamides, which needs to be activated mainly by CYP2B6.
Expression of CYP enzymes has been shown to sensitize cells to both cyclophosphamide in a range of cell lines in vitro and the bystander effect is mediated through the soluble derivative 4-hydroxycyclophosphamide.
Hepatic P enzymes like CYP2B6 or CYP2B1 as well as P reductase have been inserted into 9L gliosarcoma cells by viral transfection in order to facilitate tumour growth suppression in cultured cells and in xenogaft models upon treatment with anticancer agents Huang et al.
In addition, a combinatory treatment of cyclophosphamide and another drug impairing the hepatic expression of P reductase and hence minimizing the hepatic activation of cyclophosphamide can be used Huang et al. In vitro and animal models showed promising effects of this approach McFadyen et al.
CYPs have important roles in activation and inactivation of both precarcinogens and of anticancer drugs see Figure 4. Interindividual differences in the P mediated actions are caused both by environmental and genetic factors. Due to the relatively high extent of conservation of genes encoding CYPs participating in the activation of precarcinogens, the genetic factors are less important determinants of individual susceptibility, whereas inducers of P s like smoking, ethanol, etc.
Here the knowledge about the different CYP alleles distributed in the populations and their functional consequences is relatively well known, whereas the impact of the polymorphism for in vivo treatment with anticancer drugs remains largely to be elucidated.
The recent achievements in using the polymorphic P as drug targets in cancer therapy are promising and could provide a novel and effective alternative of future cancer therapy. Xenobiotic metabolizing CYP enzymes and cancer. Class I enzymes are in general well conserved and active in the metabolism of precarcinogens and drugs, while Class II enzymes have important functional polymorphisms and are active in the metabolism of drugs, but not of precarcinogens. Class I P s are important for the aetiology of cancer diseases, while Class II P s play an important role in cancer therapy.
Agundez JA. Curr Drug Metab 5 : — Mol Pharmacol 64 : — Mol Pharmacol 61 : — Cancer Res 65 : — J Pharmacol Exp Ther : — Cancer Epidemiol Biomarkers Prev 11 : — Bournique B, Lemarie A. Drug Metab Dispos 30 : — Carcinogenesis 24 : — Mol Cell Biol 21 : — Oncogene 22 : — Anticancer Drugs 16 : — Pharmacogenetics 11 : — Pharmacogenetics 12 : — Pharmacogenetics 13 : — J Clin Oncol 23 : — Clin Pharmacokinet 41 : — J Clin Oncol 21 : — Clin Cancer Res 11 : — Clin Pharmacol Ther 75 : — J Clin Oncol 17 : — Pharmacogenomics J 5 : — Pharmacogenetics 9 : — Mol Cancer Ther 2 : — J Clin Oncol 20 : — Gonzalez FJ.
Drug Metab Rev 35 : — Mol Pharmacol 60 : — Carcinogenesis 13 : — Mutat Res : — Br J Clin Pharmacol 54 : — However, a functional effect of this variant has not been established 3. Hepatic and intestinal expression of CYP3A4 exhibits a unimodal distribution of activity suggesting that the population variability is not due to genetic polymorphism of the enzyme itself 2.
Nevertheless, there are indications of substantial heritability3. Variation in CYP3A4 among healthy individuals is most likely to be the result of differences in homeostatic regulatory mechanisms 2. In disease states, the inherent variability of CYP3A4 mediated drug metabolism is potentially exacerbated by many factors including alterations in hepatic haemodynamics, hepatocellular function, nutrition, circulating hormones, as well as drug-drug interactions 2,3.
It has also been increasingly recognised that inflammatory mediators associated with a range of disease states are capable of having profound effects on CYP3A4 gene expression 2. Patients with inflammation, particularly elevated acute phase proteins such as C-reactive protein CRP have been noted to have reduced CYP3A4 function 2.
This is clinically relevant in cancer patients because tumours can be a source of systemically circulating cytokines 3. Acute systemic hypoxia eg, in chronic respiratory or cardiac insufficiency appears to up-regulate CYP3A4 activity 7. CYP3A4 is subject to reversible and mechanism-based irreversible inhibition. The latter involves the inactivation of the enzyme via the formation of metabolic intermediates that bind irreversibly to the enzyme and then inactivate it 6.
The clinical effects of a mechanistic inactivator are more prominent after multiple dosing and last longer than those of a reversible inhibitor 6. Medicines that are potent CYP3A4 inhibitors include but are not limited to clarithromycin, diltiazem, erythromycin, itraconazole, ketoconazole, ritonavir, and verapamil 9. One form of reversible inhibition occurs due to competition between CYP3A4 substrates eg, oestrogen and antidepressants during the late luteal phase of the menstrual cycle 4.
The magnitude of CYP3A4 induction can be substantial. Induction becomes apparent more slowly than inhibition and it takes more time for the induction to stop affecting medicine metabolism. For example, the induction of CYP3A4 by rifampicin takes around six days to develop and 11 days to disappear
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