Changes in CYP enzymes are acknowledged to be a frequent aftermath stimulation of the immune system following infection and inflammation 18 — 21 and in most cases there is no additional sign of toxicity of affected organs.
CYP2C18 is expressed at very low levels in liver tissue, and so it is unaffected by cytokine exposure. Moreover, data strongly suggest that even with the overlapping effects of cytokines, the activity of human Ps is independently regulated in infection and inflammation.
However, the differentiation in inflammatory response to cytokines may be crucial for patient treatment, since it is estimated that CYPs enzymes are distinctly regulated at different stages by various mechanisms, as a result to inflammation or disease. This foreknowledge is enhanced by the different sensitivity of CYP-dependent clearance revealed by infectious liver disease Cytochromes P enzymes are involved in the metabolism of a large pool of xenobiotic substances.
Activation of cytochromes CYPs enzymes is influenced by a plethora of factors, such as genus, environment, disease state, alcohol consumption, and herbal medications In this frame, multiple isoforms of CYP have been linked to drug pharmacokinetics, carcinogenesis, steroids, and prostaglandins metabolism As discussed previously, both P activity and level are affected by infection and inflammation, specifically by cytokines released during activation of the immune system.
Interferons and proinflammatory cytokines can downregulate P expression ex vivo in hepatocyte cultures and in vivo , and these modulators are believed to be the reason of P downregulation in the inflammatory process Drug—drug interactions can occur during anticancer therapy with interferon or ILs. Cytochromes P enzymes are activated by specific substances and agents The decrease in catalytic activity was associated in most cases with a proportional decrease in protein and in mRNA levels 3.
As discussed, infections or inflammation cause alterations in the expression levels and activities of various forms of P in the liver, as well as in other extrahepatic tissues such as kidney and brain However, in most cases, the activity of CYPs is inhibited. It must be also noted that the effects of inflammatory mediators are not limited only to infections with live organisms or inflammatory ailments: interferons are used in cancer treatment and antiviral therapy, and various other cytokines are under in vivo investigation for cancer treatment 3 , It must be highlighted that the modulation of CYP P by inflammatory cytokines was extensively studied in cultured rat hepatocytes Moreover, studies performed to detect the effects of cytokines on cultured human hepatocytes 35 — 37 showed effects identical to those observed in rat hepatocytes However, it was reported that important levels of CYP2A6 were found in postmortem specimens of liver infected with hepatitis B or C virus in infected cells or cells found in areas proximity of fibrosis or inflammation 31 harbored.
In patients with advanced cancer the downregulation is linked to CYP3A4 39 and in animal model systems is mediated via IL-6 derived from the tumor itself 9. In the light of the above, it is clear that more research is needed to clarify these conflicting results and the effects of the different infectious or inflammatory diseases on the expression and activities of different human P enzymes. This was the case when an influenza epidemic lead to a reduced clearance of theophylline in children taking asthma medication Vaccination and immune stimulation seem to play a critical role.
Drug metabolism is compromised in humans with impaired immune system after inflammation or vaccination Toxicity could be induced due to enhanced pharmacological responses as a result of the downregulation of drug metabolizing enzymes by the cytochromes, in the patients with infections or following vaccination or in cancer patients receiving interferon or in patients under cytokine therapy It must also be reported that patients receiving anticonvulsants or theophylline, which require systematic monitoring of their serum levels, often seem to have an impaired drug metabolism after vaccination Influenza virus vaccination downregulate CYP 1A2 enzymes expression In immunodeficiency virus-positive patients CYP 2D6 enzymes expression was also decreased Cytokines linked to effector T-cell responses can alter the regulation of many drug transporters as well as CYP enzymes levels.
Immune-modulating antibodies used in cancer therapy may have effects on CYP enzymes It seems that there is a close connection between obesity, immunity, and inflammation 46 , 47 , as many CYP enzymes are expressed in the adipose tissue 48 , Obese hospitalized patients seem to develop more frequently endonosocomial infections.
Mortality of obese patients with severe sepsis was higher compared with non-obese patients 48 , Genetic predisposition seems to be a critical factor.
Chronic, heavy alcohol exposure contributes to major pathophysiological effects associated to ethanol and inflammation of the adipose tissue, insulin resistance, and liver injury. Moreover, ethanol feeding increased CYP2E1 expression in adipocytes Aged mice whose retina was exposed briefly to nm light, which increases mitochondrial membrane potential and reduces inflammation showed significant increases in levels of cytochrome c oxidase, which is a mitochondrial enzyme modulating oxidative phosphorylation It was also reported that the phagocytic activity and secretory capacity of Kupffer cells is closely associated with increased immune reactions and downregulated expression of some hepatic cytochrome CYP In the same time, the inhibition of Kupffer cell by GdCl3 gadolinium chloride exerted anti-obesity effects in high-fat diet-fed mice All these data show that obese individuals are not only more susceptible to infections, but also have a greater risk for adverse drug reactions due to impaired drug metabolism and kinetics To date, there is not much information available to discriminate between the expression of CYPs in acute versus chronic inflammation.
The expression of different CYP isoenzymes was studied by Muntane et al. The CYP represent a superfamily of enzymes with a key role in the activation or inactivation of a plethora of therapeutic agents.
CYP enzymes are involved in the metabolism of xenobiotic substances. Cytochromes present intra- or interindividual and intra- or interethnic genetic polymorphisms. Variations in the pharmacokinetic drug profile are linked to the rising toxicity following a declining metabolism, reduced efficacy of the drug, adverse drug interaction, and increasing production of toxic metabolites. The high-metabolic rate of the intestinal microbiota is due to its many enzymes which catalyze reactions in phase I and II drug metabolism.
In case of a compromised intestinal barrier, there may be an increase in paracellular passive absorption. It is evident that high-microbial abundance following intestinal disturbances, environment, aging, or food-associated diseases promotes the microbial metabolism of a drug before absorption.
Recently, the beneficial effect of certain microbes on the intestinal ecosystem has been largely discussed. The aim of probiotics is to restore the deficiencies in the intestinal microbiota and establish a protective effect. There is a multifactorial association of the CYP enzyme role in the different disease states, nutritional status, and environmental toxic effects.
CYP cytochromes keep a key role in cancer formation and cancer treatment as they activate numerous precarcinogens and participate in the inactivation and activation of anticancer drugs However, the question is raised, which specific variant of the CYP alleles should be related to the different type of cancers?
As discussed extensively, many of the CYP are modulated by injury and infection. It is known that cytokines are useful markers in certain inflammatory diseases.
Albeit, IL-6 deletion seems to weaken the downregulation of certain CYP enzymes in mice under inflammatory stimuli regimen. It is then conceivable that cytokines cannot be the unique biomarker of an inflammatory disease. Acute phase proteins, as well as other metabolomics and proteomic markers need to be determined in order to reveal the infectious status and confirm diagnosis ES wrote the manuscript, GP made figures, corrected and submitted the manuscript, EB drafted the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer VL declared a past co-authorship with one of the authors EB to the handling editor. Immunosenescence of ageing. J Pathol 2 — Bezirtzoglou E.
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 For example, Lucey et al.
CYP3A activity, using the [ 14 C] erythromycin breath test, was reduced compared with that in controls, including other liver transplant recipients. Pretreatment with rifampicin, an inducer of CYP3A,increased enzyme activity.
After treatment with rifampicin the patient was able to be rechallenged with cyclosporin at a dose almost twice that which had previously been toxic. The patient died during a second transplantation and the microsomal CYP3A content was found to be low in the first transplant liver.
Lower blood levels of cyclosporin may have been achieved when the drug used for enzyme induction rifampicin has been given to the transplant patient for a long period [ ]. Rifampicin [ 98 — , , ] and isoniazid [ ] are key drugs used in the treatment of tuberculosis, while rifampicin is highly effective in inducing hepatic, drug metabolic P enzyme. When enzyme induction is achieved, the pharmacological effects of a specific drug may be reduced, since not only the metabolism of rifampicin itself, but also the metabolism of the other drug is accelerated [ ].
The problem arises when doses are increased to reduce the effects of the combined drugs: increased serum concentrations of the combined drugs may possibly produce side-effects because of the lost enzyme induction if rifampicin is discontinued. As for dihydropyridine calcium channel blockers, it is quite possible that interactions with rifampicin may develop,since most of these drugs are metabolized by CYP3A4 [ — , ]. There are two main types of drug interaction: pharmacokinetic and pharmacodynamic.
Pharmacokinetic interactions involve the effect of one drug on the absorption,metabolism, excretion or protein binding of another drug. On the other hand,pharmacodynamic interactions are caused by several effects additive, synergistic or antagonistic effects of the combined treatment at the site of biological activity,changing the pharmacological action of the drugs, even at standard blood concentrations.
Pharmacokinetic interactions focused on P are described in this paper. The incidence of side-effects is markedly higher in the elderly and those with more severe symptoms. Thus, understanding the mechanism underlying drug interactions is useful, not only in preventing drug toxicity or adverse effects, but also in devising safer therapies for disease. Guengerich FP: Characterization of human cytochrome P enzyme.
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