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Among epithelial ovarian cancers, ovarian clear cell carcinoma (OCCC) remains markedly resistant to platinum-based chemotherapy, leading to poor clinical outcomes. In response to xenobiotic insults, caveolar platforms play crucial roles in modulating stress signaling responses in cancer cells. It has been hypothesized that caveolin-1 (Cav-1), a main component of the lipid raft, may regulate the response to platinum-based treatment in OCCC. The clinical transcriptomic evaluation demonstrated that high Cav-1 expression was positively associated with a favorable prognosis in patients with ovarian cancer. Cav-1 overexpression enhanced sensitivity to cisplatin (CDDP) treatment, whereas Cav-1 deficiency promoted chemoresistance in OCCC cells. Mechanistically, although Cav-1 counteracted angiotensin-converting enzyme 2 (ACE2) expression, ACE2 positively facilitated resistance to CDDP in OCCC cells. Furthermore, ACE2 restricted aryl hydrocarbon receptor expression and subsequent transcription of drug-metabolizing enzymes. Of note, ACE2 positively regulated the expression of the platinum-clearing enzyme CYP3A4. These findings suggest that the Cav-1-ACE2 axis modulates xenobiotic metabolism-linked chemoresistance in OCCC, predicting potential roles for the stress sentinel networks in oncogenic processes., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

The structural variability data of drug transporter (DT) are key for research on precision medicine and rational drug use. However, these valuable data are not sufficiently covered by the available databases. In this study, a major update of VARIDT (a database previously constructed to provide DTs' variability data) was thus described. First, the experimentally resolved structures of all DTs reported in the original VARIDT were discovered from PubMed and Protein Data Bank. Second, the structural variability data of each DT were collected by literature review, which included: (a) mutation-induced spatial variations in folded state, (b) difference among DT structures of human and model organisms, (c) outward/inward-facing DT conformations and (d) xenobiotics-driven alterations in the 3D complexes. Third, for those DTs without experimentally resolved structural variabilities, homology modeling was further applied as well-established protocol to enrich such valuable data. As a result, 145 mutation-induced spatial variations of 42 DTs, 1622 inter-species structures originating from 292 DTs, 118 outward/inward-facing conformations belonging to 59 DTs, and 822 xenobiotics-regulated structures in complex with 57 DTs were updated to VARIDT (https://idrblab.org/varidt/ and http://varidt.idrblab.net/). All in all, the newly collected structural variabilities will be indispensable for explaining drug sensitivity/selectivity, bridging preclinical research with clinical trial, revealing the mechanism underlying drug-drug interaction, and so on., (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Environmental factors including diet, sedentary lifestyle and exposure to pollutants largely influence human health throughout life. Cellular and molecular events triggered by an exposure to environmental pollutants are extremely variable and depend on the age, the chronicity and the doses of exposure. Only a fraction of all relevant mechanisms involved in the onset and progression of pathologies in response to toxicants has probably been identified. Mitochondria are central hubs of metabolic and cell signaling responsible for a large variety of biochemical processes, including oxidative stress, metabolite production, energy transduction, hormone synthesis, and apoptosis. Growing evidence highlights mitochondrial dysfunction as a major hallmark of environmental insults. Here, we present mitochondria as crucial organelles for healthy metabolic homeostasis and whose dysfunction induces critical adverse effects. Then, we review the multiple mechanisms of action of pollutants causing mitochondrial toxicity in link with chronic diseases. We propose the Aryl hydrocarbon Receptor (AhR) as a model of "exposome receptor", whose activation by environmental pollutants leads to various toxic events through mitochondrial dysfunction. Finally, we provide some remarks related to mitotoxicity and risk assessment.

Rice bran oil (RBO) comprises various nutrients and phytochemicals which exhibit several health benefits. There are no studies regarding the functional effects of different colours of RBO. This study was aimed to compare the constituents and antioxidant activities of white rice bran oil (WRBO) and coloured rice bran oil (CRBO). Each RBO showed similar free fatty acid profiles. However, greater amounts of vitamin E, phytosterols, carotenoids, and chlorophylls were found in CRBO, which had lower γ -oryzanol content than WRBO. Oxidative stress was induced in male mice by an overdose of acetaminophen (APAP) at 300 mg/kg body weight. The mice were then fed with RBO at the equivalent dose to 100 mg/kg body weight of γ -oryzanol three hours later and sacrificed six hours after APAP treatment. The administration of 100 mg γ -oryzanol equivalent in CRBO ameliorated APAP-induced hepatotoxicity in mice more strongly than 100 mg γ -oryzanol equivalent in WRBO, as evidenced by the significant reduction of serum ALT, hepatocellular necrosis, and hepatic lipid peroxidation. CRBO could improve xenobiotic-metabolizing and antioxidant enzyme activities, including glutathione S -transferase, superoxide dismutase, glutathione peroxidase, and glutathione reductase, and also increase mRNA expression of various antioxidant-responsive genes. Vitamin E, phytosterols, carotenoids, and chlorophyll might be the protective compounds in CRBO that alleviate APAP-induced hepatotoxicity through the interruption of APAP metabolism and the activation of antioxidant systems at both transcriptional and enzymatic levels. These findings might provide a protective role of CRBO on oxidative stress associated with several degenerative diseases., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2021 Warunyoo Phannasorn et al.)

Previous studies have revealed that genetic polymorphisms of the Glutathione S-transferase M1 and T1 (GSTM1 and GSTT1), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6) are associated with the presence of non-alcoholic fatty liver disease (NAFLD) in many populations. This study was conducted to investigate the association of the GSTM1, GSTT1, TNF-α rs1800629, and IL-6 rs1800795 with NAFLD in the general Iranian population. A case-control analysis included 242 NAFLD patients and 324 healthy controls from Iranian adults. After the physical examination, the genotypes were determined by polymerase chain reaction(PCR). The GSTM1 null, GSTT1 null, TNF-α AG/AA, and IL-6 CG/CC genotypes were deemed to be high-risk. The null allele of GSTM1 and A allele of TNF-α were more frequent in NAFLD patients even after Bonferroni's correction (P values<0.005, adjusted odds ratio (OR), 1.66 and 2.02; 95% confidence intervals (CI), (1.18-2.32) and (1.34-3.34), respectively. The IL-6 CC/CG genotype association with NAFLD was not significant after correction (P value = 0.04) Polymorphisms of xenobiotic and pro-inflammatory genes are associated with NAFLD in the Iranian population and seem to be a useful tool for NAFLD prevention and care.

Review of the use of nonexperimental xenobiotics in terrestrial animal models and the potential unintended consequences of these compounds, including drug-related side effects and adverse reactions., (© The Author(s) 2020. Published by Oxford University Press on behalf of the National Academies of Sciences, Engineering, and Medicine. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Pharmacological treatment and exposure to xenobiotics can cause substantial changes in epigenetic signatures. The majority of these epigenetic changes, caused by the compounds in question, occur downstream of transcriptional activation mechanisms, whereby the epigenetic alterations can create a transcriptional memory and stably modulate cell function. The increasing understanding of epigenetic mechanisms and their importance in disease has prompted the development of therapeutic interventions that target epigenetic modulatory mechanisms, particularly in oncology where inhibitors of epigenetic-modifying proteins (epidrugs) have been successfully used in treatment, mostly in combination with standard-of-care chemotherapy, either provoking direct cytotoxicity or inhibiting resistance to anticancer drugs. In addition, emerging methods for detecting epigenetically modified DNA in bodily fluids may provide information about tumor phenotype or drug treatment success. However, it is important to note that many technical pitfalls, such as the nondeconvolution of methylcytosine and hydroxymethylcytosine, compromise epigenetic analyses and the interpretation of results. In this review, we provide an update on the field, with an emphasis on the novel therapeutic opportunities made possible by epidrugs.

NR1I2 (PXR) and NR1I3 (CAR) are nuclear receptors that are classified as xenoreceptors. Upon activation by various xenobiotics, including marketed drugs, they regulate the transcription level of major drug-metabolizing enzymes and transporters and facilitate the elimination of xenobiotics from the body. The modulation of the activity of these two xenoreceptors by various ligands is a major source of pharmacokinetic variability of environmental origin. NR1I2 and NR1I3 genetic polymorphisms can affect the pharmacokinetics and therapeutic response to many drugs, such as irinotecan, tacrolimus and atazanavir. This review provides an overview of NR1I2 and NR1I3 pharmacogenetic studies in various therapeutic fields (oncology, immunomodulation and infectiology) and discusses the implementation of NR1I2 and NR1I3 genetic polymorphism testing in the clinical routine.

Organismal fitness depends on adaptation to complex niches where chemical compounds and pathogens are omnipresent. These stresses can lead to the fixation of alleles in both xenobiotic responses and proliferative signaling pathways that promote survival in these niches. However, both xenobiotic responses and proliferative pathways vary within and among species. For example, genetic differences can accumulate within populations because xenobiotic exposures are not constant and selection is variable. Additionally, neutral genetic variation can accumulate in conserved proliferative pathway genes because these systems are robust to genetic perturbations given their essential roles in normal cell-fate specification. For these reasons, sensitizing mutations or chemical perturbations can disrupt pathways and reveal cryptic variation. With this fundamental view of how organisms respond to cytotoxic compounds and cryptic variation in conserved signaling pathways, it is not surprising that human patients have highly variable responses to chemotherapeutic compounds. These different responses result in the low FDA-approval rates for chemotherapeutics and underscore the need for new approaches to understand these diseases and therapeutic interventions. Model organisms, especially the classic invertebrate systems of Caenorhabditis elegans and Drosophila melanogaster, can be used to combine studies of natural variation across populations with responses to both xenobiotic compounds and chemotherapeutics targeted to conserved proliferative signaling pathways., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Drug and xenobiotic metabolizing enzymes (DXME) play important roles in drug responses and carcinogenesis. Recent studies have found that expression of DXME in cancer cells significantly affects drug clearance and the onset of drug resistance. In this study we compared the expression of DXME in breast tumor tissue samples from patients representing three ethnic groups: Caucasian Americans (CA), African Americans (AA), and Asian Americans (AS). We further combined DXME gene expression data with eQTL data from the GTEx project and with allele frequency data from the 1000 Genomes project to identify SNPs that may be associated with differential expression of DXME genes. We identified substantial differences among CA, AA, and AS populations in the expression of DXME genes and in activation of pathways involved in drug metabolism, including those involved in metabolizing chemotherapy drugs that are commonly used in the treatment of breast cancer. These data suggest that differential expression of DXME may associate with health disparities in breast cancer outcomes observed among these three ethnic groups. Our study suggests that development of personalized treatment strategies for breast cancer patients could be improved by considering both germline genotypes and tumor specific mutations and expression profiles related to DXME genes.

Extrahepatic cytochrome P450 enzymes (CYP450) are pivotal in the metabolism of endogenous substrates and xenobiotics. CYP2J2 is a major cardiac CYP450 and primarily metabolizes polyunsaturated fatty acids such as arachidonic acid to cardioactive epoxyeicosatrienoic acids. Due to its role in endobiotic metabolism, CYP2J2 has been actively studied in recent years with the focus on its biological functions in cardiac pathophysiology. Additionally, CYP2J2 metabolizes a number of xenobiotics such as astemizole and terfenadine and is potently inhibited by danazol and telmisartan. Notably, CYP2J2 is found to be upregulated in multiple cancers. Hence a number of specific CYP2J2 inhibitors have been developed and their efficacy in inhibiting tumor progression has been actively studied. CYP2J2 inhibitor such as C26 (1-[4-(vinyl)phenyl]-4-[4-(diphenyl-hydroxymethyl)-piperidinyl]-butanone hydrochloride) caused marked reduction in tumor proliferation and migration as well as promoted apoptosis in cancer cells. In this review, we discuss the role of CYP2J2 in cardiac pathophysiology and cancer therapeutics. Additionally, we provide an update on the substrates, reversible inhibitors and irreversible inhibitors of CYP2J2. Finally, we discuss the current gaps and future directions in CYP2J2 research., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Inflammatory bowel diseases (IBDs) are diseases characterized by various degrees of inflammation involving the gastrointestinal tract. Ulcerative colitis and Crohn's disease are characterized by a dysregulated immune response leading to structural gut alterations in genetically predisposed individuals. Diverticular disease is characterized by abnormal immune response to normal gut microbiota. IBDs are linked to a lack of physiological tolerance of the mucosal immune system to resident gut microbiota and pathogens. The disruption of immune tolerance involves inflammatory pathways characterized by an unbalance between the anti-inflammatory regulatory T cells and the proinflammatory Th1/Th17 cells. The interaction among T cell subpopulations and their related cytokines, mediators of inflammation, gut microbiota, and the intestinal mucosa constitute the gut "immunological niche." Several evidences have shown that xenobiotics, such as rifaximin, can positively modulate the inflammatory pathways at the site of gut immunological niche, acting as anti-inflammatory agents. Xenobiotics may interfere with components of the immunological niche, leading to activation of anti-inflammatory pathways and inhibition of several mediators of inflammation. In summary, xenobiotics may reduce disease-related gut mucosal alterations and clinical symptoms. Studying the complex interplay between gut immunological niche and xenobiotics will certainly open new horizons in the knowledge and therapy of intestinal pathologies.

Carboxylesterases (CESs) play major roles in catalyzing the hydrolysis of a wide range of ester- and amide-containing compounds. CESs dominate both the biotransformation of numerous therapeutic drugs and the detoxification of environmental toxicants, and the activity alteration of CESs may be a determinant reason for modification of the resultant pharmacokinetic/pharmacodynamic profile when two or more drugs are concurrently used. Herein, we provide a comprehensive review of the current literature involving of induction and inhibition on CESs by both exogenous and endogenous compounds. In particular, the inhibition constant and inhibition pattern of inhibitors on CESs in studies using animal microsomes or human recombinant CESs are summarized. Further studies are needed to clarify the underlying regulation mechanism, and alterations in CESs activity should be taken into consideration for safe clinical therapy.

Clinically, the therapeutic outcomes in neurodegenerative disorders (NDs) by drug treatment are very limited, and the most insurmountable obstacle in the treatment of NDs is the blood-brain barrier (BBB), which provides the highest level of protection from xenobiotics. A great deal of attention still needs to be paid to overcome these barriers, and surface-engineered polymeric nanoparticles are emerging as innovative tools that are able to interact with the biological system at a molecular level for the desired response. The present review covers the potential importance of surface-structure-engineered nanoparticles to overcome the BBB for good bioavailability, and the evaluation of drug therapy in NDs.

It is now very much clear that the microbiome plays an important part in human health. Microbiome is associated with several diseases and targeting the whole microbiome is certainly a challenge before the scientists. The "Human Microbiome Project" is continually exploring certain therapeutic targets inside microbiome landscape that could be utilized for the treatment of microbiome associated diseases. Additionally, associated research across the globe is going on and now some potential targets are available that might be beneficial for the designing and synthesis of novel drugs. In this review, we made an effort to discuss all the potential targets and corresponding possible drugs/treatments available for each of them. However, it is not possible to treat all microbiome associated diseases with a single drug/drug combination. Therefore, for different diseases, different treatments/drugs (whether xenobiotic or non-xenobiotic) could be used for better therapeutic efficacy.

There is growing recognition that glial proinflammatory activation importantly contributes to the rewarding and reinforcing effects of a variety of drugs of abuse, including cocaine, methamphetamine, opioids, and alcohol. It has recently been proposed that glia are recognizing, and becoming activated by, such drugs as a CNS immunological response to these agents being xenobiotics; that is, substances foreign to the brain. Activation of glia, primarily microglia, by various drugs of abuse occurs via toll like receptor 4 (TLR4). The detection of such xenobiotics by TLR4 results in the release of glial neuroexcitatory and neurotoxic substances. These glial products of TLR4 activation enhance neuronal excitability within brain reward circuitry, thereby enhancing their rewarding and reinforcing effects. Indeed, selective pharmacological blockade of TLR4 activation, such as with the non-opioid TLR4 antagonist (+)-naltrexone, suppresses a number of indices of drug reward/reinforcement. These include: conditioned place preference, self-administration, drugprimed reinstatement, incubation of craving, and elevations of nucleus accumbens shell dopamine. Notably, TLR4 blockade fails to alter self-administration of food, indicative of a selective effect on drugs of abuse. Genetic disruption of TLR4 signaling recapitulates the effects of pharmacological TLR4 blockade, providing converging lines of evidence of a central importance of TLR4. Taken together, multiple lines of evidence converge to raise TLR4 as a promising therapeutic target for drug abuse.

A large number of physiologically functional foods are comprised of plant polyphenols. Their antioxidative activities have been intensively studied for a long period and proposed to be one of the major mechanisms of action accounting for their health promotional and disease preventive effects. Green tea polyphenols (GTPs) are considered to possess marked anti-oxidative properties and versatile beneficial functions, including anti-inflammation and cancer prevention. On the other hand, some investigators, including us, have uncovered their toxicity at high doses presumably due to pro-oxidative properties. For instance, both experimental animal studies and epidemiological surveys have demonstrated that GTPs may cause hepatotoxicity. We also recently showed that diets containing high doses (0.5-1%) of a GTP deteriorated dextran sodium sulfate (DSS)-induced intestinal inflammation and carcinogenesis. In addition, colitis mode mice fed a 1% GTP exhibited symptoms of nephrotoxicity, as indicated by marked elevation of serum creatinine level. This diet also increased thiobarbituric acid-reactive substances, a reliable marker of oxidative damage, in both kidneys and livers even in normal mice, while the expression levels of antioxidant enzymes and heat shock proteins (HSPs) were diminished in colitis and normal mice. Intriguingly, GTPs at 0.01% and 0.1% showed hepato-protective activities, i.e., they significantly suppressed DSS-increased serum aspartate aminotransferase and alanine aminotransferase levels. Moreover, those diets remarkably restored DSS-down-regulated expressions of heme oxygenase-1 and HSP70 in livers and kidneys. Taken together, while low and medium doses of GTPs are beneficial in colitis model mice, unwanted side-effects occasionally emerge with high doses. This dose-dependent functionality and toxicity of GTPs are in accordance with the concept of hormesis, in which mild, but not severe, stress activates defense systems for adaptation and survival., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Multidrug resistance presents one of the most important causes of cancer treatment failure. Numerous in vitro and in vivo data have made it clear that multidrug resistance is frequently caused by enhanced expression of ATP-binding cassette (ABC) transporters. ABC transporters are membrane-bound proteins involved in cellular defense mechanisms, namely, in outward transport of xenobiotics and physiological substrates. Their function thus prevents toxicity as carcinogenesis on one hand but may contribute to the resistance of tumor cells to a number of drugs including chemotherapeutics on the other. Within 48 members of the human ABC superfamily there are several multidrug resistance-associated transporters. Due to the well documented susceptibility of numerous drugs to efflux via ABC transporters it is highly desirable to assess the status of ABC transporters for individualization of treatment by their substrates. The multidrug resistance associated protein 1 (MRP1) encoded by ABCC1 gene is one of the most studied ABC transporters. Despite the fact that its structure and functions have already been explored in detail, there are significant gaps in knowledge which preclude clinical applications. Tissue-specific patterns of expression and broad genetic variability make ABCC1/MRP1 an optimal candidate for use as a marker or member of multi-marker panel for prediction of chemotherapy resistance. The purpose of this review was to summarize investigations about associations of gene and protein expression and genetic variability with prognosis and therapy outcome of major cancers. Major advances in the knowledge have been identified and future research directions are highlighted.

The heart is a target organ for oxidative stress-related injuries. Because of its very high energetic metabolic demand, the heart has the highest rate of production of reactive oxygen species, namely, hydrogen peroxide (H2O2), per gram of tissue. Additionally, the heart has lower levels of antioxidants and total activity of antioxidant enzymes when compared to other organs. Furthermore, drugs that have relevant antioxidant activity and that are used in the treatment of oxidative stress related cardiac diseases demonstrate better clinical cardiac outcomes than other drugs with similar receptor affinity but with no antioxidant activity. Several xenobiotics particularly target the heart and promote toxicity. Anticancer drugs, like anthracyclines, cyclophosphamide, mitoxantrone, and more recently tyrosine kinase targeting drugs, are well-known cardiac toxicants whose therapeutic application has been associated to a high prevalence of heart failure. High levels of catecholamines or drugs of abuse, namely, amphetamines, cocaine, and even the consumption of alcohol for long periods of time, are linked to cardiovascular abnormalities. Oxidative stress may be one common link for the cardiac toxicity elicited by these compounds. We aim to revise the mechanisms involved in cardiac lesions caused by the above-mentioned substances specially focusing in oxidative stress related pathways. Oxidative stress biomarkers can be useful in the early recognition of cardiotoxicity in patients treated with these drugs and aid to minimize the setting of cardiac irreversible events.

Retinoic acid (RA), the active metabolite of vitamin A, is an important endogenous signaling molecule regulating cell cycle and maintenance of epithelia. RA isomers are also used as drugs to treat various cancers and dermatological diseases. However, the therapeutic uses of RA isomers are limited due to side effects such as teratogenicity and resistance to treatment emerging mainly from autoinduction of RA metabolism. To improve the therapeutic usefulness of retinoids, RA metabolism blocking agents (RAMBAs) have been developed. These inhibitors generally target the cytochrome P450 (CYP) enzymes because RA clearance is predominantly mediated by P450s. Since the initial identification of inhibitors of RA metabolism, CYP26 enzymes have been characterized as the main enzymes responsible for RA clearance. This makes CYP26 enzymes an attractive target for the development of novel therapeutics for cancer and dermatological conditions. The basic principle of development of CYP26 inhibitors is that endogenous RA concentrations will be increased in the presence of a CYP26 inhibitor, thus, potentiating the activity of endogenous RA in a cell-type specific manner. This will reduce side effects compared to administration of RA and allow for more targeted therapy. In clinical trials, inhibitors of RA metabolism have been effective in treatment of psoriasis and other dermatological conditions as well as in some cancers. However, no CYP26 inhibitor has yet been approved for clinical use. This review summarizes the history of development of RAMBAs, the clinical and preclinical studies with the various structural series and the available knowledge of structure activity relationships of CYP26 inhibitors.

The steroids and xenobiotics receptor (SXR) up-regulates the expression and the synthesis of key enzymes in CyA metabolism. In this study, we examined the possible interactions between CyA exposure and SXR polymorphisms during the first year after renal transplantation. The study involved 66 pediatric renal transplant recipients (25 women and 41 men, mean age 13.9 ± 7.4 yr). All patients were genotyped for two sequence variations in the NR1I2 gene: g.-205&#95;-200delGAGAAG and 7635 A>G. CyA trough levels and CyA weight-adjusted daily dose were recorded at 30, 90, 180, and 360 days after transplantation and compared between the different genotypes. A third newly discovered SXR polymorphism was characterized and also included in the study. CyA trough levels and CyA weight-adjusted daily dose were comparable on four time points throughout the first year post-transplant in all three groups. GEE showed a significant reduction in weight-adjusted CyA daily dose in patients carrying the deletion of 6 bp in SXR with a significant group-by-time effect that persisted also when analysis was corrected for age, prednisone dose, and acute rejection episodes. In our group of patients, only the g.-205&#95;-200delGAGAAG SXR polymorphism was able to influence the metabolism of CyA continuously, during the first year after transplantation., (© 2012 John Wiley & Sons A/S.)

Immunosuppression is the mayor mechanism to prevent allograft rejection and to induce tolerance. Since the first solid organ transplant, the development of safe and effective immunosuppressive regimens was a constant over the last decades. A lot of immunosuppressants have been discovered, and today the immunosuppressive agents are classified in two broad groups: Xenobiotic immunosuppressants and biological immunosuppressants. Xenobiotics, like corticoids and calcineurin and mTOR inhibitors, mainly interfere with the intracellular molecular mechanisms of the various types of cells involved in the immune response and generally these immunosuppressants are used early on in the transplantation process to prevent rejection as well as in long-term maintenance therapy. On the other hand, target molecules of biological immunosuppressants are on the surface of these immunological cells and normally in clinical immunosuppressive protocols have been used as auxiliary agents of xenobiotics to prevent rejection as well as in the treatment of acute rejection. However, these xenobiotics and biological agents have multiple side effects; that is why there has been a search for new drugs to minimise these side effects and to improve patients' quality of life. In this way, new biological agents have been proposed as maintenance immunosuppressive agents. The majority of these new immunosuppressive agents are polyclonal or monoclonal antibodies and recently the so-called fusion proteins may be the start of a new era of biological immunosuppression for maintenance regimens.

Evidence from both epidemiological and experimental observations has fuelled the belief that the high consumption of fruits and vegetables rich in nutrients and phytochemicals may help prevent cancer and heart disease in humans. This concept has been drastically simplified from the dietary approaches to the use of single bioactive components both as a single supplement or in functional foods to manipulate xenobiotic metabolism. These procedures, which aim to induce mutagen/carcinogen detoxification or inhibit their bioactivation, fail to take into account the multiple and paradoxical biological outcomes of enzyme modulators that make their effects unpredictable. Here, we show that the idea that the physiological roles of specific catalysts may be easily manipulated by regular long-term administration of isolated nutrients and other chemicals derived from food plants is not viable. In contrast, we claim that the consumption of healthy diets is most likely to reduce mutagenesis and cancer risk, and that both research endeavours and dietary recommendations should be redirected away from single molecules to dietary patterns as a main strategy for public health policy.

The objective of this study was to determine whether genetic polymorphisms in enzymes that metabolise oxidative agents modify the individual susceptibility to developing asbestos and smoking-related pleuropulmonary changes. Nine polymorphisms of six genes (EPHX1, GSTM1, GSTM3, GSTP1, GSTT1 and NAT2) were genotyped from 1,008 Finnish asbestos-exposed workers. The genotype data were compared to signs of lung fibrosis and pleural thickenings, as well as with total lung capacity, single-breath diffusing capacity of the lung for carbon monoxide (D(L,CO)) and specific diffusing capacity (expressed as D(L,CO) per unit of alveolar volume (V(A))). The GSTT1 deletion polymorphism was associated with fibrotic changes (p=0.003), and decreased D(L,CO) (p=0.02) and D(L,CO)/V(A) (p=0.002), and the GSTM1 deletion polymorphism was associated with the greatest thickness of pleural plaques (p=0.009). On further analysis, the GSTT1 null genotype was found to pose over a three-fold risk for severe fibrotic changes (OR 3.12, 95% CI 1.51-6.43), and around two-fold risks for decreased D(L,CO) (OR 1.77, 95% CI 1.06-2.95) and D(L,CO)/V(A) (OR 2.37, 95% CI 1.33-4.23). In addition, the GSTM1 null genotype showed an elevated risk (OR 1.36, 95% CI 1.03-1.80) for thicker pleural plaques. Our data suggest that inherited detoxification capacity may affect the development and severity of asbestos and smoking-related nonmalignant pulmonary changes.

Unlabelled: Viral infections are often linked to altered drug metabolism in patients; however, the underlying molecular mechanisms remain unclear. Here we describe a mechanism by which activation of antiviral responses by the synthetic double-stranded RNA ligand, polyinosinic-polycytidylic acid (polyI:C), leads to decreased acetaminophen (APAP) metabolism and hepatotoxicity. PolyI:C administration down-regulates expression of retinoic X receptor-α (RXRα) as well as its heterodimeric partner pregnane X receptor (PXR) in mice. This down-regulation results in suppression of downstream cytochrome P450 enzymes involved in conversion of APAP to its toxic metabolite. Although the effects of polyI:C on drug metabolism are often attributed to interferon production, we report that polyI:C can decrease APAP metabolism in the absence of the type I interferon receptor. Furthermore, we demonstrate that polyI:C can attenuate APAP metabolism through both its membrane-bound receptor, Toll-like receptor 3 (TLR3), as well as cytoplasmic receptors., Conclusion: This is the first study to illustrate that in vivo administration of polyI:C affects drug metabolism independent of type I interferon production or in the absence of TLR3 through crosstalk between nuclear receptors and antiviral responses., (Copyright © 2011 American Association for the Study of Liver Diseases.)

The androgen receptor (AR) is a member of nuclear receptor superfamily (NRs) and plays a critical role in prostate cancer development and progression. Therefore, anti-androgens that repress AR activity remain a critical mainstay for prostate cancer therapy. However, molecular mechanisms by which anti-androgens exert their therapeutic effects are not clearly elucidated and hence are a major area of scientific pursuit. Here, we demonstrate that another member of NRs, pregnane and xenobiotic receptor (PXR), not only acts as a molecular sensor of anti-androgens but also influences the outcome of therapeutic regimen with anti-androgenic drugs via a novel AR-PXR cross-talk. Using 'gain- and loss-of-function' studies, we identified a distinct role of PXR as a potent repressor of AR-regulated transcription. Our study implicates PXR as a key determinant of anti-androgen action since down-regulation of PXR diminishes the potency of the anti-androgenic drugs and enhances transcriptional actions of androgens. In addition, our subcellular localization studies revealed that ligand-activated AR induces nuclear localization of PXR and the two receptors colocalize at discrete sites in nucleus and mitotic chromatin. Finally, we report a distinct antagonist-induced interaction between AR and PXR defining a hitherto unidentified mode of action of AR antagonist. In this perspective, the study may help in designing and development of novel AR antagonists offering improved avenues in prostate cancer therapy., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Antioxidants have been shown to provide protection against carcinogens, toxic xenobiotics and oxidative stress. This has led to the hypothesis that the addition of antioxidants to cancer chemotherapeutic regimens could increase their efficacy while reducing the side effects often encountered during treatment. The work described in this study set out to test this hypothesis using two different chemotherapeutics, Paclitaxel and FUdR, and three different antioxidants, epigallocatechin gallate, phenethyl isothiocyanate and tert-butylhydroquinone. Experiments were carried out on two different breast carcinoma cell lines, MCF-7 and MDA MB435S. Importantly, we did not observe an enhancement of the efficacy of the chemotherapeutic agents in the twelve combinations tested. In fact, for several combinations, simultaneous treatment with an antioxidant attenuated the efficacy of the chemotherapeutic agent. We also determined that the survival advantage provided by antioxidants is consistent with their ability to induce the expression of genes whose regulatory regions contain antioxidant response elements. Together, these findings suggest that the simultaneous use of antioxidants and chemotherapeutic agents has the potential to attenuate the efficacy of chemotherapy by inducing the expression of enzymes that can detoxify cytotoxic agents. In view of these findings, we suggest that the design of chemotherapeutic regimens that combine antioxidants with chemotherapeutic agents should be considered carefully before being initiated.

We presented the method of treatment of acute poisoning with some substances which is based on izocapnic hyperpnea. It seems that this method may be useful in the treatment of poisoning with various xenobiotics.

In this review, intratumoral drug disposition will be integrated into the wide range of resistance mechanisms to anticancer agents with particular emphasis on targeted protein kinase inhibitors. Six rules will be established: 1. There is a high variability of extracellular/intracellular drug level ratios; 2. There are three main systems involved in intratumoral drug disposition that are composed of SLC, ABC and XME enzymes; 3. There is a synergistic interplay between these three systems; 4. In cancer subclones, there is a strong genomic instability that leads to a highly variable expression of SLC, ABC or XME enzymes; 5. Tumor-expressed metabolizing enzymes play a role in tumor-specific ADME and cell survival and 6. These three systems are involved in the appearance of resistance (transient event) or in the resistance itself. In addition, this article will investigate whether the overexpression of some ABC and XME systems in cancer cells is just a random consequence of DNA/chromosomal instability, hypo- or hypermethylation and microRNA deregulation, or a more organized modification induced by transposable elements. Experiments will also have to establish if these tumor-expressed enzymes participate in cell metabolism or in tumor-specific ADME or if they are only markers of clonal evolution and genomic deregulation. Eventually, the review will underline that the fate of anticancer agents in cancer cells should be more thoroughly investigated from drug discovery to clinical studies. Indeed, inhibition of tumor expressed metabolizing enzymes could strongly increase drug disposition, specifically in the target cells resulting in more efficient therapies.

Increasing attention is being paid to the possibility of applying chemopreventive agents for the protection of individuals from cancer risk. The beneficial potential of chemoprotective compounds is usually well documented by extensive experimental data. To assure the desired effect, these compounds are frequently concentrated to produce dietary supplements for human use. The additive and synergistic effects of other food constituents are, however, frequently ignored. Even natural chemopreventive compounds have to be considered as xenobiotics. Thus, as much attention has to be paid to their testing prior to their wide application as is usual in drug development for human treatment. Unfortunately, much of the research in this area is solely based on simplified in vitro systems that cannot take into account the complexity of biotransformation processes, e.g. chemopreventive compound-drug interaction, effect on metabolism of endogenic compounds. Hence, the predicted chemopreventive potential is not attained in respect of cancer prevention; moreover, the administration of high doses of chemopreventive compounds might be even detrimental for the human health.

The farnesoid X receptor (FXR) is a member of ligand-activated nuclear receptor superfamily. FXR is a bile sensor and is part of a complex network of nuclear receptors that includes also the constitutive androstane receptor and the pregnane X receptor. These receptors act coordinately to regulate essential steps of bile acids and xenobiotics uptake, metabolism and excretion in hepatocytes, cholangiocytes and kidney cells. Preclinical models indicate that FXR agonists are effective in reducing liver injury in nonobstructive models of cholestasis. FXR ligands are currently under investigation for treating patients with early stage primary biliary cirrhosis. Although these ligands hold promise, evidence is growing that FXR activation could impair the expression/activity of basolateral transporters such as multidrug resistance protein 4 essential for basolateral secretion of bile constituents in the systemic circulation. Because FXR, pregnane X receptor and constitutive androstane receptor ligands interact with different target genes, it appear that a combination with pregnane X receptor, constitutive androstane receptor ligand/activator or both or ursodeoxycholic acid could prevent possible side-effects of FXR activation in severe cholestasis.

The idea that low-dose adaptive effects as described in hormesis can be used clinically has been discussed for hundreds if not thousands of years. Paracelsus famous adage that ;the dose makes the poison' and the common folk saying that one can be cured by ;the hair of the dog that bit you' speak to this idea. So why has so little research been done on the possible clinical utility of hormesis? What areas of clinical hormesis seem to be the most promising to explore? This article examines these concepts and proposes some initial areas or research where the possible utility of hormeiss might be investigated.

The article deals with topics associated with contemporary state of using specialized food products to correct metabolic processes in intoxication with various chemicals.

The long interval which occurs between the initiation and the development of clinically defined cancer is a characteristic feature of carcinogenesis and other degenerative diseases in experimental models and in humans. This makes early intervention possible. In the last half century, the role of xenobiotic metabolism in the induction carcinogenesis has been thoroughly described. Recent research using new tools provide data helpful in understanding the mechanism of induction and convincing proof that selective induction of phase II enzymes is an effective way of protecting cells against reactive carcinogenic metabolites and reactive oxygen species. These results create a foundation for applying this approach as a chemopreventive and chemoprotective strategy. S-transferase glutathione and reductase NAD(P)H-quinone are enzymes of concern. In this paper the characteristics and function of these two enzymatic systems are presented as well as the mechanism of induction of compounds, which induce phase II enzymes and act as potential chemopreventive agents.

The Ah receptor (AhR) is a ligand-activated transcription factor and member of the bHLH/PAS (basic helix-loop-helix/Per-Arnt-Sim) family of chemosensors and developmental regulators. It represents a multifunctional molecular switch involved in regulation of endo- and xenobiotic metabolism, in vascular development and in dioxin-mediated toxicities. Recently, the oxidative stress-protecting Nrf2 has been shown to be a downstream target of the AhR [Miao W, Hu L, Scrivens PJ, Batist G. Transcriptional regulation of NF-E2 p45-regulated factor (NRF2) expression by the aryl hydrocarbon receptor-xenobiotic response element signaling pathway. J Biol Chem 2005;280:20340-8]. This finding offers the possibility that distinct but partially overlapping AhR and Nrf2 gene batteries of Phase II xenobiotic-metabolizing enzymes can be synergistically activated by a number of phytochemicals, acting as selective or mixed activators of target genes. In addition, it is conceivable that AhR-mediated oxidative/electrophile stress may be attenuated by coupled Nrf2 activation. The commentary discusses potentials and limitations of (i) selective Nrf2 and of (ii) synergistic AhR plus Nrf2 activation by phytochemicals in efforts towards chemoprevention of cancer and degenerative diseases, and describes clinical trials providing the expectation that chemopreventive measures may favorably modulate unavoidable endo- and exogenous toxin exposures in high risk populations.

Spirulina, a filamentous cyanobacterium, possesses diverse biological activities and nutritional significance due to high concentration of natural nutrients, having bio-modulatory and immuno-modulatory functions. Different Spirulina preparations influence immune system viz. increase phagocytic activity of macrophages, stimulating the production of antibodies and cytokines, increase accumulation of NK cells into tissue and activation and mobilization of T and B cells. Spirulina have also shown to perform regulatory role on lipid and carbohydrate metabolism by exhibiting glucose and lipid profile correcting activity in experimental animals and in diabetic patients. Preparations have been found to be active against several enveloped viruses including herpes virus, cytomegalovirus, influenza virus and HIV. They are capable to inhibit carcinogenesis due to anti-oxidant properties that protect tissues and also reduce toxicity of liver, kidney and testes.

Introduction: Astrocytes are involved in multiple brain functions in physiological conditions. Cytochromes P450 are expressed in astrocytes and play a role in brain metabolism and in neuroprotection., Background: Although the levels of various cytochromes P450 in brain regions are low, these enzymes were reported to be expressed at relatively high level in astroglial cells and may play a critical role in the biotransformation of endogenous or exogenous compounds. Astroglial cytochromes P450 expression suggests a putative capacity to metabolize psychoactive or lipophilic xenobiotics in situ, associated with pharmacological and/or toxicological consequences. Astrocytes appear to be the most active steroidogenic cells in the brain, expressing neurosteroïdogenic cytochromes P450 and producing various neurosteroids. Cytochrome P450 epoxygenase enzymes, which catalyze the formation of vasoactive compounds are also present in astrocytes, contributing to the regulation of the cerebral blood flow., Perspectives and Conclusion: This review underlines the crucial roles of astroglial cytochromes P450 in brain functions. Identification of the molecular mechanisms involved in the regulation of these enzymes could open therapeutic perspectives and improve our understanding in neuroprotection.

The onset or exacerbation of psoriasis, a T-cell-dependent skin disease with autoimmune features, can be triggered by drugs such as antimalarials and beta-blockers. Xenobiotics may also play a role in idiopathic psoriasis. It has been hypothesized that different metabolic efficiencies caused by variant alleles of xenobiotic metabolizing enzymes could lead to the accumulation of xenobiotics or their reactive metabolites in target organs. Subsequently, neoantigens or cryptic peptides could be presented and initiate an aggressive T cell response. In this context, we analyzed a broad array of xenobiotic metabolizing enzymes in up to 327 Caucasian psoriasis patients and compared them to 235 control persons. Alleles tested include four phase I and three phase II enzymes. Significantly more carriers of the variant alleles of CYP1A1 (alleles *2A and *2C) were found in healthy controls than in patients, suggesting a protective role for these alleles. No significant difference between patients and controls could be found, however, for the other phase I alleles 1B1*1 and 1B1 *3, 2C19*1A and 2C19*2A, and 2E1*1A and 2E1*5B. Of the variant alleles coding for phase II enzymes only GSTM1, but not GSTT1 or NQOR, correlated with a risk to contract psoriasis. Some combinations of phase I and phase II enzymes suggested protective or risk-associated effects. Interestingly, heterozygosity for CYP2C19 alleles *1A and *2A was associated with increased risk for "late onset" psoriasis, whereas this genotype was protective for psoriatic arthritis. This is the first large-scale study on these enzymes and the results obtained support the concept that different activities of metabolizing enzymes can contribute to disease etiology and progression.

Xenobiotic resistance is the major cause of failure in human therapies. Because of their serious clinical and economical consequences, resistance phenomena have been intensively studied in the case of antibacterial, anticancer, antipaludic and anti-human immunodeficiency virus-1 therapies. Beside pharmacological factors that can impede the action of the drugs, several cellular mechanisms of resistance have been described. Surprisingly, these mechanisms are conserved among bacteria, eucaryotic cells, parasites and viruses. The efficiency of drugs can be circumvented by alteration of the drug cellular concentration (altered influx, enhanced efflux or sequestration), detoxification, alteration of the drug target, nonactivation or inactivation of the drug, or by enhanced DNA repair.

An unprecedented arsenal of new xenobiotic immunosuppressive agents has been developed recently. Most of the new immunosuppressants have been tested primarily in the treatment of allograft rejection in experimental models of transplantation, and some of the new drugs have already proven their safety and efficiency in extensive clinical trials on transplant patients. Another field for their potential application is the treatment of autoimmune diseases. This review will give an overview of the therapeutic potential of the new xenobiotic drugs in different animal models of rheumatoid arthritis, systemic lupus erythematosus, myasthenia gravis, multiple sclerosis, diabetes mellitus, thyroiditis and uveoretinitis. The new xenobiotics are either inhibitors of the de novo synthesis of nucleotides, for example mycophenolate mofetil, mizoribine, leflunomide, and brequinar, or are immunophilin-binding agents (cyclosporin, FK506 and rapamycin) that inhibit signal transduction and cell cycle progression in lymphocytes. A different mode of action is likely to account for the immunosuppressive effects of deoxyspergualin, which may interfere with intracellular chaperoning by the heat shock protein HSP70 and the activation of transcription factor NF-kappa B.