Neuroactive steroids fluctuate with regional specificity in the central and peripheral nervous system across the rat estrous cycle.

Neuroactive steroids (i.e., sex steroid hormones and neurosteroids) are important physiological regulators of nervous function and potential neuroprotective agents for neurodegenerative and psychiatric disorders. Sex is an important component of such effects. However, even if fluctuations in sex steroid hormone level during the menstrual cycle are associated with neuropathological events in some women, the neuroactive steroid pattern in the brain across the ovarian cycle has been poorly explored. Therefore, we assessed the levels of pregnenolone, progesterone, and its metabolites (i.e., dihydroprogesterone, allopregnanolone and isoallopregnanolone), dehydroepiandrosterone, testosterone and its metabolites (i.e., dihydrotestosterone, 3α-diol and 17ß-estradiol) across the rat ovarian cycle to determine whether their plasma fluctuations are similar to those occurring in the central (i.e., hippocampus and cerebral cortex) and peripheral (i.e., sciatic nerve) nervous system. Data obtained indicate that the plasma pattern of these molecules generally does not fully reflect the events occurring in the nervous system. In addition, for some neuroactive steroid levels, the pattern is not identical between the two brain regions and between the brain and peripheral nerves. Indeed, with the exception of progesterone, all other neuroactive steroids assessed here showed peculiar regional differences in their pattern of fluctuation in the nervous system during the estrous cycle. These observations may have important diagnostic and therapeutic consequences for neuropathological events influenced by the menstrual cycle.

Gut Steroids and Microbiota: Effect of Gonadectomy and Sex.

Sex steroids, derived mainly from gonads, can shape microbiota composition; however, the impact of gonadectomy and sex on steroid production in the gut (i.e., gut steroids), and its interaction with microbiota composition, needs to be clarified. In this study, steroid environment and gut steroidogenesis were analysed by liquid chromatography tandem mass spectrometry and expression analyses. Gut microbiota composition as branched- and short-chain fatty acids were determined by 16S rRNA gene sequence analysis and gas chromatography flame ionisation detection, respectively. Here, we first demonstrated that levels of pregnenolone (PREG), progesterone (PROG), and isoallopregnanolone (ISOALLO) were higher in the female rat colon, whereas the level of testosterone (T) was higher in males. Sexual dimorphism on gut steroidogenesis is also reported after gonadectomy. Sex, and more significantly, gonadectomy, affects microbiota composition. We noted that a number of taxa and inferred metabolic pathways were associated with gut steroids, such as positive associations between Blautia with T, dihydroprogesterone (DHP), and allopregnanolone (ALLO), whereas negative associations were noted between Roseburia and T, ALLO, PREG, ISOALLO, DHP, and PROG. In conclusion, this study highlights the novel sex-specific association between microbiota and gut steroids with possible relevance for the gut-brain axis.

Zc3h10 regulates adipogenesis by controlling translation and F-actin/mitochondria interaction.

The commitment of mesenchymal stem cells to preadipocytes is stimulated by hormonal induction. Preadipocytes induced to differentiate repress protein synthesis, remodel their cytoskeleton, and increase mitochondrial function to support anabolic pathways. These changes enable differentiation into mature adipocytes. Our understanding of the factors that coordinately regulate the early events of adipocyte differentiation remains incomplete. Here, by using multipronged approaches, we have identified zinc finger CCCH-type containing 10 (Zc3h10) as a critical regulator of the early stages of adipogenesis. Zc3h10 depletion in preadipocytes resulted in increased protein translation and impaired filamentous (F)-actin remodeling, with the latter detrimental effect leading to mitochondrial and metabolic dysfunction. These defects negatively affected differentiation to mature adipocytes. In contrast, Zc3h10 overexpression yielded mature adipocytes with remarkably increased lipid droplet size. Overall, our study establishes Zc3h10 as a fundamental proadipogenic transcription factor that represses protein synthesis and promotes F-actin/mitochondria dynamics to ensure proper energy metabolism and favor lipid accumulation.

"The Loss of Golden Touch": Mitochondria-Organelle Interactions, Metabolism, and Cancer.

Mitochondria represent the energy hub of cells and their function is under the constant influence of their tethering with other subcellular organelles. Mitochondria interact with the endoplasmic reticulum, lysosomes, cytoskeleton, peroxisomes, and nucleus in several ways, ranging from signal transduction, vesicle transport, and membrane contact sites, to regulate energy metabolism, biosynthetic processes, apoptosis, and cell turnover. Tumorigenesis is often associated with mitochondrial dysfunction, which could likely be the result of an altered interaction with different cell organelles or structures. The purpose of the present review is to provide an updated overview of the links between inter-organellar communications and interactions and metabolism in cancer cells, with a focus on mitochondria. The very recent publication of several reviews on these aspects testifies the great interest in the area. Here, we aim at (1) summarizing recent evidence supporting that the metabolic rewiring and adaptation observed in tumors deeply affect organelle dynamics and cellular functions and vice versa; (2) discussing insights on the underlying mechanisms, when available; and (3) critically presenting the gaps in the field that need to be filled, for a comprehensive understanding of tumor cells' biology. Chemo-resistance and druggable vulnerabilities of cancer cells related to the aspects mentioned above is also outlined.

Lipidomic analysis of cancer cells cultivated at acidic pH reveals phospholipid fatty acids remodelling associated with transcriptional reprogramming.

Cancer cells need to modulate the biosynthesis of membrane lipids and fatty acids to adapt themselves to an accelerated rate of cell division and survive into an extracellular environment characterised by a low pH. To gain insight this crucial survival process, we investigated the lipid composition of Mel 501 melanoma cells cultured at either physiological or acidic pH and observed the remodelling of phospholipids towards longer and more unsaturated acyl chains at low pH. This modification was related to changes in gene expression profile, as we observed an up-regulation of genes involved in acyl chain desaturation, elongation and transfer to phospholipids. PC3 prostate and MCF7 breast cancer cells adapted at acidic pH also demonstrated phospholipid fatty acid remodelling related to gene expression changes. Overall findings clearly indicate that low extracellular pH impresses a specific lipid signature to cells, associated with transcriptional reprogramming.

Hepatic ERα accounts for sex differences in the ability to cope with an excess of dietary lipids.

OBJECTIVE: Among obesity-associated metabolic diseases, non-alcoholic fatty liver disease (NAFLD) represents an increasing public health issue due to its emerging association with atherogenic dyslipidemia and cardiovascular diseases (CVDs). The lower prevalence of NAFLD in pre-menopausal women compared with men or post-menopausal women led us to hypothesize that the female-inherent ability to counteract this pathology might strongly rely on estrogen signaling. In female mammals, estrogen receptor alpha (ERα) is highly expressed in the liver, where it acts as a sensor of the nutritional status and adapts the metabolism to the reproductive needs. As in the male liver this receptor is little expressed, we here hypothesize that hepatic ERα might account for sex differences in the ability of males and females to cope with an excess of dietary lipids and counteract the accumulation of lipids in the liver. METHODS: Through liver metabolomics and transcriptomics we analyzed the relevance of hepatic ERα in the metabolic response of males and females to a diet highly enriched in fats (HFD) as a model of diet-induced obesity. RESULTS: The study shows that the hepatic ERα strongly contributes to the sex-specific response to an HFD and its action accounts for opposite consequences for hepatic health in males and females. CONCLUSION: This study identified hepatic ERα as a novel target for the design of sex-specific therapies against fatty liver and its cardio-metabolic consequences.

Centella asiatica L. Phytosome Improves Cognitive Performance by Promoting Bdnf Expression in Rat Prefrontal Cortex.

A wide range of people in the world use natural remedies as primary approaches against illnesses. Accordingly, understanding the mechanisms of action of phytochemicals has become of great interest. In this context, Centella asiatica L. is extensively used, not only as anti-inflammatory or antioxidant agent but also as brain tonic. On this basis, the purpose of this study was to evaluate whether the chronic administration of C. asiatica L. to adult male rats was able to improve the expression of Bdnf, one of the main mediators of brain plasticity. Moreover, we assessed whether the treatment could affect the cognitive performance in the novel object recognition (NOR) test. We confirmed the presence of the main compounds in the plasma. Furthermore, C. asiatica L. administration induced an increase of Bdnf in the prefrontal cortex, and the administration of the higher dose of the extract was able to improve cognitive performance. Finally, the increase in the preference index in the NOR test was paralleled by a further increase in Bdnf expression. Overall, we highlight the ability of C. asiatica L. to affect brain functions by increasing Bdnf expression and by enhancing the cognitive performance.

Untargeted Metabolomics to Go beyond the Canonical Effect of Acetylsalicylic Acid.

Given to its ability to irreversibly acetylate the platelet cyclooxygenase-1 enzyme, acetylsalicylic acid (ASA) is successfully employed for the prevention of cardiovascular disease. Recently, an antitumoral effect of ASA in colorectal cancer has been increasingly documented. However, the molecular and metabolic mechanisms by which ASA exerts such effect is largely unknown. Using a new, untargeted liquid chromatography-mass spectrometry approach, we have analyzed urine samples from seven healthy participants that each ingested 100 mg of ASA once daily for 1 week. Of the 2007 features detected, 25 metabolites differing after ASA ingestion (nominal p < 0.05 and variable importance in projection (VIP) score > 1) were identified, and pathway analysis revealed low levels of glutamine and of metabolites involved in histidine and purine metabolisms. Likewise, consistent with an altered fatty acid ß-oxidation process, a decrease in several short- and medium-chain acyl-carnitines was observed. An abnormal ß-oxidation and a lower than normal glutamine availability suggests reduced synthesis of acetyl-Co-A, as they are events linked to one another and experimentally related to ASA antiproliferative effects. While giving an example of how untargeted metabolomics allows us to explore new clinical applications of drugs, the present data provide a direction to be pursued to test the therapeutic effects of ASA-e.g., the antitumoral effect-beyond cardiovascular protection.

DNA damage and transcription stress cause ATP-mediated redesign of metabolism and potentiation of anti-oxidant buffering.

Accumulation of DNA lesions causing transcription stress is associated with natural and accelerated aging and culminates with profound metabolic alterations. Our understanding of the mechanisms governing metabolic redesign upon genomic instability, however, is highly rudimentary. Using Ercc1-defective mice and Xpg knock-out mice, we demonstrate that combined defects in transcription-coupled DNA repair (TCR) and in nucleotide excision repair (NER) directly affect bioenergetics due to declined transcription, leading to increased ATP levels. This in turn inhibits glycolysis allosterically and favors glucose rerouting through the pentose phosphate shunt, eventually enhancing production of NADPH-reducing equivalents. In NER/TCR-defective mutants, augmented NADPH is not counterbalanced by increased production of pro-oxidants and thus pentose phosphate potentiation culminates in an over-reduced redox state. Skin fibroblasts from the TCR disease Cockayne syndrome confirm results in animal models. Overall, these findings unravel a mechanism connecting DNA damage and transcriptional stress to metabolic redesign and protective antioxidant defenses.

Ketogenic Diet: A New Light Shining on Old but Gold Biochemistry.

Diets low in carbohydrates and proteins and enriched in fat stimulate the hepatic synthesis of ketone bodies (KB). These molecules are used as alternative fuel for energy production in target tissues. The synthesis and utilization of KB are tightly regulated both at transcriptional and hormonal levels. The nuclear receptor peroxisome proliferator activated receptor α (PPARα), currently recognized as one of the master regulators of ketogenesis, integrates nutritional signals to the activation of transcriptional networks regulating fatty acid ß-oxidation and ketogenesis. New factors, such as circadian rhythms and paracrine signals, are emerging as important aspects of this metabolic regulation. However, KB are currently considered not only as energy substrates but also as signaling molecules. ß-hydroxybutyrate has been identified as class I histone deacetylase inhibitor, thus establishing a connection between products of hepatic lipid metabolism and epigenetics. Ketogenic diets (KD) are currently used to treat different forms of infantile epilepsy, also caused by genetic defects such as Glut1 and Pyruvate Dehydrogenase Deficiency Syndromes. However, several researchers are now focusing on the possibility to use KD in other diseases, such as cancer, neurological and metabolic disorders. Nonetheless, clear-cut evidence of the efficacy of KD in other disorders remains to be provided in order to suggest the adoption of such diets to metabolic-related pathologies.

Epigenome modifiers and metabolic rewiring: New frontiers in therapeutics.

In the last decade numerous publications highlighted the connection between metabolism and epigenetics in different physiological and pathological conditions. The availability of metabolites for cells represents indeed a crucial factor, which is able to condition cell fate and development, differentiation and proliferation partially trough epigenetic control. This tight link provides novel therapeutic possibilities to treat many pathological conditions induced by epigenetic alterations, by manipulating metabolic pathways producing metabolites that work also as epigenetic modifiers. This review will explore specifically the relevance of epigenetics and metabolism in the onset of metabolic disorders and cancer, highlighting potential epigenetic-based pharmacological approaches for the treatment of these disorders trough a rewiring of cellular metabolism. We will also report recent studies on stem cells, demonstrating how epigenetic setting is influenced by metabolism and how these processes affect cell pluripotency and differentiation capacity. These findings suggest a big pharmacological potential, as the modulation of epigenetics and metabolism in stem cells may represent a new tool for regenerative medicine, offering a plethora of novel possibilities for the treatment of severe pathological conditions.

Enhanced axonal neuregulin-1 type-III signaling ameliorates neurophysiology and hypomyelination in a Charcot-Marie-Tooth type 1B mouse model.

Charcot-Marie-Tooth (CMT) neuropathies are a group of genetic disorders that affect the peripheral nervous system with heterogeneous pathogenesis and no available treatment. Axonal neuregulin 1 type III (Nrg1TIII) drives peripheral nerve myelination by activating downstream signaling pathways such as PI3K/Akt and MAPK/Erk that converge on master transcriptional regulators of myelin genes, such as Krox20. We reasoned that modulating Nrg1TIII activity may constitute a general therapeutic strategy to treat CMTs that are characterized by reduced levels of myelination. Here we show that genetic overexpression of Nrg1TIII ameliorates neurophysiological and morphological parameters in a mouse model of demyelinating CMT1B, without exacerbating the toxic gain-of-function that underlies the neuropathy. Intriguingly, the mechanism appears not to be related to Krox20 or myelin gene upregulation, but rather to a beneficial rebalancing in the stoichiometry of myelin lipids and proteins. Finally, we provide proof of principle that stimulating Nrg1TIII signaling, by pharmacological suppression of the Nrg1TIII inhibitor tumor necrosis factor-alpha-converting enzyme (TACE/ADAM17), also ameliorates the neuropathy. Thus, modulation of Nrg1TIII by TACE/ADAM17 inhibition may represent a general treatment for hypomyelinating neuropathies.

Clinical outcomes of oral metronomic vinorelbine in advanced non-small cell lung cancer: correlations with pharmacokinetics and MDR1 polymorphisms.

PURPOSE: This study investigated correlations of the clinical outcomes of oral metronomic vinorelbine (VNR) with VNR pharmacokinetics and MDR1 polymorphisms. METHODS: Eighty-two patients with metastatic non-small cell lung cancer (NSCLC) unfit for standard chemotherapy were treated with VNR at the oral doses of 20-30 mg every other day or 50 mg three times a week. They had a performance status (PS) ≤ 3, were > 70-year-old and drug-naïve or cisplatin-pretreated. MDR1 2677G > T and 3435C > T polymorphisms were analysed and blood concentrations of VNR and desacetyl-VNR (dVNR: active metabolite) assayed. Overall survival (OS), treatment duration and drug-related toxicity were the main endpoints. RESULTS: Median OS and treatment duration were 27 weeks (range 1.3-183) and 15 weeks (range 1.3-144), respectively. OS was directly correlated with the duration of VNR treatment and number of therapy lines after VNR treatment (multiple linear regression: adjusted r2 = 0.71; p < 0.00001). Neither MDR1 genotypes nor VNR/dVNR concentrations predicted OS. VNR blood levels were positively correlated with platelet counts (r2 = 0.12; p = 0.0036). Patients who had long-term benefit (treated for ≥ 6 month without toxicity) showed lower VNR concentrations than those who had not. Twelve patients stopped therapy due to grade 3-4 toxicity. Toxicity was associated with blood concentrations of VNR ≥ 1.57 ng/mL and dVNR ≥ 3.04 ng/mL, but not with MDR1 polymorphisms. CONCLUSIONS: Neither pharmacokinetic nor pharmacogenetic monitoring seem useful to predict OS. On the other hand, high VNR and dVNR blood levels were associated with severe toxicity.

Interplay between Plasmodium falciparum haemozoin and L-arginine: implication for nitric oxide production.

BACKGROUND: Plasmodium falciparum haemozoin, a detoxification product of digested haemoglobin from infected erythrocytes, is released into the bloodstream upon schizont rupture and accumulates in leukocytes. High levels of haemozoin correlate with disease severity. Some studies have shown that concentrations of the substrate of inducible nitric oxide synthase (iNOS), L-arginine, as well as nitric oxide are low in patients infected with P. falciparum malaria. The present study investigates, in vitro, the role of P. falciparum haemozoin on nitric oxide production, iNOS expression in macrophages, and the possible interaction between L-arginine and haemozoin. METHODS: Plasmodium falciparum haemozoin was obtained from in vitro cultures through magnetic isolation. Phagocytosis of haemozoin by immortalized bone marrow derived macrophages was detected by confocal reflection combined with fluorescence microscopy. Nitrite concentrations in the supernatants was evaluated by Griess assay as a standard indication of nitric oxide production, while iNOS expression was detected on cell extracts by western blotting. Detection of L-arginine in haemozoin-treated or untreated media was achieved by liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: Haemozoin synergizes in vitro with interferon-gamma to produce nitric oxide. However, when mouse macrophages were stimulated with haemozoin, a proportional increase of nitric oxide was observed up to 25 µM of haemozoin, followed by a decrease with doses up to 100 µM, when nitric oxide release was completely abrogated. This was not due to reactive oxygen species production, nor to an effect on iNOS activity. Interestingly, when at 24 h, haemozoin-treated macrophages were washed and incubated in fresh medium for further 24 h, the nitric oxide production was restored in a dose-response manner. Similar results were seen when L-arginine-enriched media was used in the stimulation. Moreover, muramyldipeptide, a strong nitric oxide inducer, was unable to activate macrophages to release nitric oxide in the presence of haemozoin-treated medium. By LC-MS/MS a complete depletion of L-arginine was observed in this haemozoin-treated, conditioned medium. CONCLUSIONS: It is proposed that haemozoin interacts with L-arginine reducing its availability for iNOS, and thus decreasing nitric oxide production. The clinical (or pathological) implications of these results are discussed.

Oncogenic H-Ras Expression Induces Fatty Acid Profile Changes in Human Fibroblasts and Extracellular Vesicles.

Extracellular vesicles (EVs) are lipid bilayer surrounded particles that are considered an additional way to transmit signals outside the cell. Lipids have not only a structural role in the organization of EVs membrane bilayer, but they also represent a source of lipid mediators that may act on target cells. Senescent cells are characterized by a permanent arrest of cell proliferation, but they are still metabolically active and influence nearby tissue secreting specific signaling mediators, including those carried by EVs. Notably, cellular senescence is associated with increased EVs release. Here, we used gas chromatography coupled to mass spectrometry to investigate the total fatty acid content of EVs released by fibroblasts undergoing H-RasV12-induced senescence and their parental cells. We find that H-RasV12 fibroblasts show increased level of monounsaturated and decreased level of saturated fatty acids, as compared to control cells. These changes are associated with transcriptional up-regulation of specific fatty acid-metabolizing enzymes. The EVs released by both controls and senescent fibroblasts show a higher level of saturated and polyunsaturated species, as compared to parental cells. Considering that fibroblasts undergoing H-RasV12-induced senescence release a higher number of EVs, these findings indicate that senescent cells release via EVs a higher amount of fatty acids, and in particular of polyunsaturated and saturated fatty acids, as compared to control cells.

Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation.

Cholesterol homeostasis has a pivotal function in regulating immune cells. Here we show that apolipoprotein E (apoE) deficiency leads to the accumulation of cholesterol in the cell membrane of dendritic cells (DC), resulting in enhanced MHC-II-dependent antigen presentation and CD4+ T-cell activation. Results from WT and apoE KO bone marrow chimera suggest that apoE from cells of hematopoietic origin has immunomodulatory functions, regardless of the onset of hypercholesterolemia. Humans expressing apoE4 isoform (ε4/3-ε4/4) have increased circulating levels of activated T cells compared to those expressing WT apoE3 (ε3/3) or apoE2 isoform (ε2/3-ε2/2). This increase is caused by enhanced antigen-presentation by apoE4-expressing DCs, and is reversed when these DCs are incubated with serum containing WT apoE3. In summary, our study identifies myeloid-produced apoE as a key physiological modulator of DC antigen presentation function, paving the way for further explorations of apoE as a tool to improve the management of immune diseases.

Short-Term Fasting Reveals Amino Acid Metabolism as a Major Sex-Discriminating Factor in the Liver.

Sex impacts on liver physiology with severe consequences for energy metabolism and response to xenobiotic, hepatic, and extra-hepatic diseases. The comprehension of the biology subtending sex-related hepatic differences is therefore very relevant in the medical, pharmacological, and dietary perspective. The extensive application of metabolomics paired to transcriptomics here shows that, in the case of short-term fasting, the decision to maintain lipid synthesis using amino acids (aa) as a source of fuel is the key discriminant for the hepatic metabolism of male and female mice. Pharmacological and genetic interventions indicate that the hepatic estrogen receptor (ERα) has a key role in this sex-related strategy that is primed around birth by the aromatase-dependent conversion of testosterone into estradiol. This energy partition strategy, possibly the result of an evolutionary pressure enabling mammals to tailor their reproductive capacities to nutritional status, is most important to direct future sex-specific dietary and medical interventions.

Oral Metronomic Vinorelbine (OMV) in elderly or pretreated patients with advanced non small cell lung cancer: outcome and pharmacokinetics in the real world.

Background Oral metronomic therapy (OMV) is particularly suitable for palliative care, and schedules adapted for unfit patients are advisable. This study investigated the effects of oral vinorelbine given every other day without interruption and its pharmacokinetic profile in patients with advanced lung cancer. Materials and Methods Ninety-two patients received OMV at doses of 20, 30 or 50 mg. Toxic events, clinical benefit and overall survival were analysed. Blood pharmacokinetics were evaluated in 82 patients. Results Median treatment duration and overall survival were 15 (range 1.3-144) and 32.3 weeks, respectively; fourty-eight (60%) patients experienced clinical benefit. Outcomes were unrelated to previous therapies, age, histology or comorbidities. Toxicity was associated with higher blood concentrations of the drug. Pharmacokinetics were stable for up to two years, and were not influenced by treatment line or age. Conclusions OMV produced non-negligible survival in patients and also showed stable long-term blood concentrations. The schedule of 20-30 mg every other day without interruption gave good tolerability and clinical benefit.

Rapid LC-MS/MS method for quantification of vinorelbine and 4-O-deacetylvinorelbine in human whole blood suitable to monitoring oral metronomic anticancer therapy.

A rapid and sensitive LC-MS/MS method for therapeutic drug monitoring oral vinorelbine (VRL) metronomic anticancer chemotherapy has been developed and validated. Analysis of VRL and its main active metabolite 4-O-deacetylvinorelbine (M1) was performed in whole blood matrix. Both analytes were extracted by protein precipitation and separated on an Onyx monolith C18 , 50 × 2 mm column then quantified by positive electrospray ionization and multiple reaction monitoring mode. The LLOQ was 0.05 ng/mL for both VRL and M1. Linearity was up to 25ng/mL with R2 ≥ 0.994. The intra- and inter-assay precisions were ≤ 11.6 and ≤ 10.4% while the ranges of accuracy were [-8.7%; 10.3%] and [-10.0; 7.4%] for VRL and M1, respectively. The clinical suitability of the method has been proved by the determination of the CTrough blood concentrations of VRL and M1 in 64 nonsmall cell lung cancer elderly patients. The analytical performance of the assay was suitable for pharmacokinetic monitoring of VRL and M1, allowing the personalization of the VRL metronomic treatments.

Sustained activation of detoxification pathways promotes liver carcinogenesis in response to chronic bile acid-mediated damage.

Chronic inflammation promotes oncogenic transformation and tumor progression. Many inflammatory agents also generate a toxic microenvironment, implying that adaptive mechanisms must be deployed for cells to survive and undergo transformation in such unfavorable contexts. A paradigmatic case is represented by cancers occurring in pediatric patients with genetic defects of hepatocyte phosphatidylcholine transporters and in the corresponding mouse model (Mdr2-/- mice), in which impaired bile salt emulsification leads to chronic hepatocyte damage and inflammation, eventually resulting in oncogenic transformation. By combining genomics and metabolomics, we found that the transition from inflammation to cancer in Mdr2-/- mice was linked to the sustained transcriptional activation of metabolic detoxification systems and transporters by the Constitutive Androstane Receptor (CAR), a hepatocyte-specific nuclear receptor. Activation of CAR-dependent gene expression programs coincided with reduced content of toxic bile acids in cancer nodules relative to inflamed livers. Treatment of Mdr2-/- mice with a CAR inhibitor blocked cancer progression and caused a partial regression of existing tumors. These results indicate that the acquisition of resistance to endo- or xeno-biotic toxicity is critical for cancers that develop in toxic microenvironments.