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Cytochrome P450 (CYP) is involved in the metabolism of a variety of anticancer drugs. CYP activities are known to be modified by several factors including genetic polymorphisms, changes in physiological conditions such as age, disease status or intake of certain drugs or foods or environmental factors such as smoking. These factors may cause interi...
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Background
Tamoxifen, a common anti-estrogen breast cancer medication, is a prodrug that undergoes bioactivation via cytochrome P450 enzymes, CYP2D6 and to a lesser degree, CYP3A4 to form the active metabolite endoxifen. With an increasing use of oral anti-cancer drugs, the risk for drug-drug interactions mediated by enzyme inhibitors and inducers...
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... One example of the latter approach is to determine cytochrome P450 enzyme activity in individual patients. Most cancer drugs are metabolized by one or more of the cytochrome P450 enyzmes (CYPs), principally those located in the endoplasmic reticulum of liver cells, though some drugmetabolizing CYPs are found in the mitochondrial membrane (Fujita, 2006;Zhao et al., 2021). Importantly, activity of these enzymes varies widely between individuals and, even in the same individual, CYP activities can change over time depending on a range of other factors. ...
... Research in precision dosing with respect to CYP activity initially focused on a pharmacogenetic approach. By identifying the presence of known CYP gene polymorphisms with different activities, the metabolism of drugs which were substrates for a given CYP subfamily was predicted (Rochat, 2005;Fujita, 2006;Shastry, 2006). This approach showed some promise as genetic polymorphisms are associated with treatment response in some cases (Seredina et al., 2012). ...
Introduction: The cytochrome P450 enzyme subfamilies, including CYP3A4 and CYP1A2, have a major role in metabolism of a range of drugs including several anti-cancer treatments. Many factors including environmental exposures, diet, diseaserelated systemic inflammation and certain genetic polymorphisms can impact the activity level of these enzymes. As a result, the net activity of each enzyme subfamily can vary widely between individuals and in the same individual over time. This variability has potential major implications for treatment efficacy and risk of drug toxicity, but currently no assays are available for routine use to guide clinical decision-making.
Methods: To address this, a mass spectrometry-based method to measure activities of CYP3A4, CYP1A2 was adapted and tested in free-living participants. The assay results were compared with the predicted activity of each enzyme, based on a self-report tool capturing diet, medication, chronic disease state, and tobacco usage. In addition, a feasibility test was performed using a low-volume dried blood spots (DBS) on two different filter-paper supports, to determine if the same assay could be deployed without the need for repeated standard blood tests.
Results: The results confirmed the methodology is safe and feasible to perform in free-living participants using midazolam and caffeine as test substrates for CYP3A4 and CYP1A2 respectively. Furthermore, though similar methods were previously shown to be compatible with the DBS format, the assay can also be performed successfully while incorporating glucuronidase treatment into the DBS approach. The measured CYP3A4 activity score varied 2.6-fold across participants and correlated with predicted activity score obtained with the self-report tool. The measured CYP1A2 activity varied 3.5-fold between participants but no correlation with predicted activity from the self-report tool was found.
Discussion: The results confirm the wide variation in CYP activity between individuals and the important role of diet and other exposures in determining CYP3A4 activity. This methodology shows great potential and future cross-sectional and longitudinal studies using DBS are warranted to determine how best to use the assay results to guide drug treatments.
... Evidently, some of these agents have various metabolic pathways and some must be activated via CYP3A4. However, theoretical interaction may not always be clinically signifcant [51][52][53][54]. For instance, concomitant administration of aprepitant with cyclophosphamide was investigated; despite increased exposure to the agent, no signifcant changes were reported in the serum concentration of its active metabolite. ...
Objectives. Although several guidelines are available aiming for optimal chemotherapy-induced nausea and vomiting (CINV) control, there still remain critical therapeutic challenges: (i) recommendations are mainly drug-based, not protocol-based; (ii) the risk of antiemetics-related interactions is not highlighted; (iii) the emetogenicity of a regimen may vary over the cycle; and (iv) the impact of the underlying malignancy is overlooked. Apparently, the existing approach seems not to be generally efficient and puts patients at risk of insufficient use of antiemetics as well as poor emesis control. Evidence Acquisition. This study has re-evaluated the emetogenicity of chemotherapy regimens based on administered medications on each day, drug-drug interactions, combination therapy, and delayed CINV. Results. A literature review was done to re-evaluate the emetogenicity of the commonly accepted chemotherapy regimens based on administered medications on each day, drug interactions, combination therapy, and delayed CINV. Conclusion. The revised CINV prophylaxis protocols with sorted recommendations for hematologic malignancies and solid tumors have been represented, with respect to the availability of prophylactic medications.
... As previously mentioned, the CYP family is involved in the metabolism of various anticancer drugs. Consequently, variations of CYP enzymes (e.g., polymorphisms, induction, and inhibition) can interfere with anticancer drug effects [86], especially because classic chemotherapy is not necessarily specific to tumor cells and also acts on healthy cells [87]. ...
The soluble fraction of polysaccharides from cabernet franc red wine (SFP) previously showed antitumoral effects by modulating the immune system. The present study tested the hypothesis that the SFP can regulate CYPs in vitro in HepG2 cells and in vivo in Walker-256 tumor-bearing rats. The SFP was used in the following protocols: (i) solid tumor, (ii) liquid tumor, and (iii) chemopreventive solid tumor. The SFP reduced solid tumor growth in both solid tumor protocols but did not inhibit liquid tumor development. The SFP reduced total CYP levels in the solid and liquid tumor protocols and reduced the gene expression of Cyp1a1 and Cyp2e1 in rats and CYP1A2 in HepG2 cells. An increase of N-acetylglucosaminidase activity was observed in all SFP-treated rats, and TNF-α levels increased in the solid tumor protocol in the vehicle, SFP, and vincristine (positive control) groups. The chemopreventive solid tumor protocol did not modify CYP levels in the liver or intestine or N-acetylglucosaminidase and myeloperoxidase activity in the liver. The in vitro digestion and nuclear magnetic resonance analyses suggested that SFP was minimally modified in the gastrointestinal system. In conclusion, SFP inhibited CYPs both in vivo and in vitro, likely as a result of its immunoinflammatory actions.
... Over 90% of clinically used drugs, including anticancer drugs, are metabolized by CYP enzymes, which are mainly expressed in the liver. 9,10) In particular, CYP3A4 is one of the major drug-metabolizing enzymes involved in the activity of 30-50% of clinically used drugs; therefore, variation in CYP3A4 activity affects drug response. 11,12) According to previous reports, including those of the U.S. Food and Drug Administration (FDA), inter-individual variability is often caused by CYP3A4 inducers and inhibitors, food-drug and drug-drug interactions, and genetic polymorphisms. ...
CYP3A4, which contributes to the metabolism of more than 30% of clinically used drugs, exhibits high variation in its activity; therefore, predicting CYP3A4 activity before drug treatment is vital for determining the optimal dosage for each patient. We aimed to develop and validate an LC-tandem mass spectrometry (LC-MS/MS) method that simultaneously measures the levels of CYP3A4 activity-related predictive biomarkers (6β-hydroxycortisol (6β-OHC), cortisol (C), 1β-hydroxydeoxycholic acid (1β-OHDCA), and deoxycholic acid (DCA)). Chromatographic separation was achieved using a YMC-Triart C18 column and a gradient flow of the mobile phase comprising deionized water/25% ammonia solution (100 : 0.1, v/v) and methanol/acetonitrile/25% ammonia solution (50 : 50 : 0.1, v/v/v). Selective reaction monitoring in the negative-ion mode was used for MS/MS, and run times of 33 min were used. All analytes showed high linearity in the range of 3–3000 ng/mL. Additionally, their concentrations in urine samples derived from volunteers were analyzed via treatment with deconjugation enzymes, ignoring inter-individual differences in the variation of other enzymatic activities. Our method satisfied the analytical validation criteria under clinical conditions. Moreover, the concentrations of each analyte were quantified within the range of calibration curves for all urine samples. The conjugated forms of each analyte were hydrolyzed to accurately examine CYP3A4 activity. Non-invasive urine sampling employed herein is an effective alternative to invasive plasma sampling. The analytically validated simultaneous quantification method developed in this study can be used to predict CYP3A4 activity in precision medicine and investigate the potential clinical applications of CYP3A4 biomarkers (6β-OHC/C and 1β-OHDCA/DCA ratios).
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... In this context, the development and subsequential evaluation of new potential anticancer compounds have been explored extensively throughout the years [4][5][6][7]. From this perspective, important bioactive molecules with prominent antitumour activity have been described [8][9][10]. Amongst these molecules, quinones in general play an important role [11][12][13][14], since they actively participate in the molecular stress generated by reactive oxygen species (ROS) [15,16], culminating ...
... From this isolated intermediate, a nucleophilic attack with sodium azide results in the desired azide 7, in a 91% yield. A six-membered azide (compound 10) may be also achieved when lapachol (8) itself is used as a substrate. A sequence of four distinguished steps, passing through an isolatable hydroxylated intermediate (9), leads to azide 10 [32], in a 93% yield. ...
... The anthraquinone-derived aminoalkyne 18e, which previously led to the final product in lower yields, was not different in this case, in which the desired product 21e was obtained in a 59% yield. 8 ...
In 2021, our research group published the prominent anticancer activity achieved through the successful combination of two redox centres (ortho-quinone/para-quinone or quinone/selenium-containing triazole) through a copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. The combination of two naphthoquinoidal substrates towards a synergetic product was indicated, but not fully explored. Herein, we report the synthesis of 15 new quinone-based derivatives prepared from click chemistry reactions and their subsequent evaluation against nine cancer cell lines and the murine fibroblast line L929. Our strategy was based on the modification of the A-ring of para-naphthoquinones and subsequent conjugation with different ortho-quinoidal moieties. As anticipated, our study identified several compounds with IC50 values below 0.5 µM in tumour cell lines. Some of the compounds described here also exhibited an excellent selectivity index and low cytotoxicity on L929, the control cell line. The antitumour evaluation of the compounds separately and in their conjugated form proved that the activity is strongly enhanced in the derivatives containing two redox centres. Thus, our study confirms the efficiency of using A-ring functionalized para-quinones coupled with ortho-quinones to obtain a diverse range of two redox centre compounds with potential applications against cancer cell lines. Here as well, it literally takes two for an efficient tango!
... The metabolism of anticancer medications is mostly controlled by the CYP2A, CYP2B, CYP2C, CYP2D, and CYP3A subfamilies. Chemoresistance is one of the most significant issues in the treatment of brain malignancies [35,36]. Intracellular drug inactivation may be caused by elevated P450 concentrations. ...
Cytochrome (CYP) enzymes catalyze the metabolism of numerous exogenous and endogenous substrates in cancer therapy leading to significant drug interactions due to their metabolizing effect. CYP enzymes play an important role in the metabolism of essential anticancer medications. They are shown to be overexpressed in tumor cells at numerous locations in the body. This overexpression could be a result of lifestyle factors, presence of hereditary variants of CYP (Bio individuality) and multi-drug resistance. This finding has sparked an interest in using CYP inhibitors to lower their metabolizing activity as a result facilitating anti-cancer medications to have a therapeutic impact. As a result of the cytotoxic nature of synthetic enzyme inhibitors and the increased prevalence of herbal medication, natural CYP inhibitors have been identified as an excellent way to inhibit overexpression sighting their tendency to show less cytotoxicity, lesser adverse drug reactions and enhanced bioavailability. Nonetheless, their effect of lowering the hindrance caused in chemotherapy due to CYP enzymes remains unexploited to its fullest. It has been observed that there is a substantial decrease in first pass metabolism and increase in intestinal absorption of chemotherapeutic drugs like paclitaxel when administered along with flavonoids which help suppress certain specific cytochrome enzymes which play a role in paclitaxel metabolism. This review elaborates on the role and scope of phytochemicals in primary, secondary and tertiary care and how targeted prevention of cancer could be a breakthrough in the field of chemotherapy and oncology. This opens up a whole new area of research for delivery of these natural inhibitors along with anticancer drugs with the help of liposomes, micelles, nanoparticles, the usage of liquid biopsy analysis, artificial intelligence in medicine, risk assessment tools, multi-omics and multi-parametric analysis. Further, the site of action, mechanisms, metabolites involved, experimental models, doses and observations of two natural compounds, quercetin & thymoquinone, and two plant extracts, liquorice & garlic on CYP enzymes have been summarized.
Graphical Abstract
... 5-FU has been reported to decrease the activities of CYPs (65), while other anticancer drugs increase these activities (66). Additionally, definitive differences between species were reported in anticancer drug metabolism (67)(68)(69). Considering the uncommon effects of anticancer drugs on CYPs and the species differences between humans and rats, the inconsistent results observed in the rat intestines and hESC-ELCs treated with 5-FU or MTX require further examination. ...
The gastrointestinal tract is the most common exposure route of xenobiotics, and intestinal toxicity can result in systemic toxicity in most cases. It is important to develop intestinal toxicity assays mimicking the human system; thus, stem cells are rapidly being developed as new paradigms of toxicity assessment. In this study, we established human embryonic stem cell (hESC)-derived enterocyte-like cells (ELCs) and compared them to existing in vivo and in vitro models. We found that hESC-ELCs and the in vivo model showed transcriptomically similar expression patterns of a total of 10,020 genes than the commercialized cell lines. Besides, we treated the hESC-ELCs, in vivo rats, Caco-2 cells, and Hutu-80 cells with quarter log units of lethal dose 50 or lethal concentration 50 of eight drugs—chloramphenicol, cycloheximide, cytarabine, diclofenac, fluorouracil, indomethacin, methotrexate, and oxytetracycline—and then subsequently analyzed the biomolecular markers and morphological changes. While the four models showed similar tendencies in general toxicological reaction, hESC-ELCs showed a stronger correlation with the in vivo model than the immortalized cell lines. These results indicate that hESC-ELCs can serve as a next-generation intestinal toxicity model.
... There are major inter-and intra-individual variations in the capacity to metabolize, detoxify and extrude xenobiotics (see below). These are of genetic, epigenetic, environmental, and physio-or pathophysiological origin, and vary during lifetime [9,13,21,[24][25][26][27][28][29]. Most xenobiotics are detoxified and cleared through an intricate network of multiple enzymes and pathways. ...
... With the advances in research during the last 30 years, it became clear that the effects of genetic variability of DMEs, particularly those of the CYP enzymes complex, are highly relevant in terms of drug response and detoxification or bioactivation of xenobiotics in general [24,26,57,59,114]. Cytochrome P450s exhibit genetic polymorphisms with multiple allelic variants, demonstrating frequencies varying between different populations and ethnicities [57][58][59]82,106,122] (Figure 4). ...
Human Cytochrome P450 (CYP) enzymes constitute a superfamily of membrane-bound hemoproteins that are responsible for the metabolism of a wide variety of clinically, physiologically, and toxicologically important compounds. These heme-thiolate monooxygenases play a pivotal role in the detoxification of xenobiotics, participating in the metabolism of many structurally diverge compounds. This short-review is intended to provide a summary on the major roles of CYPs in Phase I xenobiotic metabolism. The manuscript is focused on eight main topics that include the most relevant aspects of past and current CYP research. Initially, (I) a general overview of the main aspects of absorption, distribution, metabolism, and excretion (ADME) of xenobiotics are presented. This is followed by (II) a background overview on major achievements in the past of the CYP research field. (III) Classification and nomenclature of CYPs is briefly reviewed, followed by (IV) a summary description on CYP’s location and function in mammals. Subsequently, (V) the physiological relevance of CYP as the cornerstone of Phase I xenobiotic metabolism is highlighted, followed by (VI) reviewing both genetic determinants and (VI) nongenetic factors in CYP function and activity. The last topic of the review (VIII) is focused on the current challenges of the CYP research field.
... CYP1B1 also influences estrogen activity, which is implicated in breast and gynecological cancers. CYP3A4 expression in bone marrow stromal cells and mesenchymal progenitor cells mediates drug resistance in hematological malignancies such as acute myeloid leukemia (AML) and multiple myeloma (MM) [21]. Thus, CYP450 enzymes play a multifaceted role in various cancers and their therapeutics. ...
Recent advances in treatment have transformed the management of cancer. Despite these advances, cardiovascular disease remains a leading cause of death in cancer survivors. Cardio-oncology has recently evolved as a subspecialty to prevent, diagnose, and manage cardiovascular side effects of antineoplastic therapy. An emphasis on optimal management of comorbidities and close attention to drug interactions are important in cardio-oncologic care. With interdisciplinary collaboration among oncologists, cardiologists, and pharmacists, there is potential to prevent and reduce drug-related toxicities of treatments. The cytochrome P450 (CYP450) family of enzymes and the P-glycoprotein (P-g) transporter play a crucial role in drug metabolism and drug resistance. Here we discuss the role of CYP450 and P-g in drug interactions in the field of cardio-oncology, provide an overview of the cardiotoxicity of a spectrum of cancer agents, highlight the role of precision medicine, and encourage a multidisciplinary treatment approach for patients with cancer.
... As previously mentioned, the CYP family is involved in the metabolism of various anticancer drugs. Consequently, variations of CYP enzymes (e.g., polymorphisms, induction, and inhibition) can interfere with anticancer drug effects [86], especially because classic chemotherapy is not necessarily specific to tumor cells and also acts on healthy cells [87]. ...
Cytochrome P450 (CYP) enzymes are responsible for the biotransformation of drugs, xenobiotics, and endogenous substances. This enzymatic activity can be modulated by intrinsic and extrinsic factors, modifying the organism’s response to medications. Among the factors that are responsible for enzyme inhibition or induction is the release of proinflammatory cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor α (TNF-α), and interferon-γ (IFN-γ), from macrophages, lymphocytes, and neutrophils. These cells are also present in the tumor microenvironment, participating in the development of cancer, a disease that is characterized by cellular mutations that favor cell survival and proliferation. Mutations also occur in CYP enzymes, resulting in enzymatic polymorphisms and modulation of their activity. Therefore, the inhibition or induction of CYP enzymes by proinflammatory cytokines in the tumor microenvironment can promote carcinogenesis and affect chemotherapy, resulting in adverse effects, toxicity, or therapeutic failure. This review discusses the relevance of CYPs in hepatocarcinoma, breast cancer, lung cancer, and chemotherapy by reviewing in vitro, in vivo, and clinical studies. We also discuss the importance of elucidating the relationships between inflammation, CYPs, and cancer to predict drug interactions and therapeutic efficacy.
