Regulation of Drug-Metabolizing Enzymes and Transporters in Inflammation

Aitken, Alison E.; Richardson, Terrilyn A.; Morgan, Edward T.

doi:10.1146/annurev.pharmtox.46.120604.141059

Cited by 403 publications

(423 citation statements)

References 143 publications

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“…Therefore, from both preclinical and clinical studies, IL-6 appears to play a central role in the downregulation of the CYP3A subfamily of enzymes in response to acute inflammation, consistent with our results (Aitken et al, 2006). The next aim of this study was to assess the impact of tumourassociated inflammation on the expression of hepatic transporters in order to ascertain whether derangement of drug disposition represents a more global phenomena occurring within the liver, involving more than drug metabolism.…”

Section: Downregulation Of Hepatic Metabolism In Malignancysupporting

confidence: 81%

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

et al. 2007

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There is increasing evidence of a systemic inflammatory response associated with malignancy, which may have an impact on both drug disposition and resistance to cytotoxic therapy. The impact of inflammation on drug disposition was studied in mice bearing a number of common tumour xenografts. C57BL/6 mice were inoculated with tumour xenografts. Hepatic expressions of Cyp3a and drug transporters were analysed at the mRNA, protein and functional levels (Cyp3a only). Circulating serum cytokines and the hepatic expression of acute phase proteins (APPs) were measured. Intratumoral levels of multidrug resistance genes were determined. Tumour xenografts elicited an inflammatory response that coincided with repression in hepatic Cyp3a11 activity and the expression of a number of hepatic drug transporters. With tumour growth, a progressive reduction in hepatic Cyp3a11 mRNA expression was seen. Conversely, an increase in the hepatic APP expression and circulating interleukin (IL)-6 levels was observed. Furthermore, a correlation was seen between increased intratumoral expression of the multidrug resistance gene, Mdr1a, and levels of circulating IL-6. Malignancy results in reduced hepatic drug disposition that correlates with an associated inflammatory response. Reduction of inflammation may improve the clinical outcome for patients receiving chemotherapeutic agents that undergo hepatic metabolism.

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Section: Downregulation Of Hepatic Metabolism In Malignancysupporting

confidence: 81%

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

et al. 2007

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“…[48] Given that CYP2E1 gene expression is under the transcriptional control of factors responsive to inflammation [19,29,49,50] it was theorized that inhibition of glycolysis in breast cancer cells bearing diverse genetic background would lead to alternative CYP2E1 cellular levels and hence dissimilar ROS. [42] On the other side inhibition of glycolysis would lead to increased ROS generation [31] that could be altered by CYP2E1 enzymatic activity.…”

Section: Discussionmentioning

confidence: 99%

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

Singh

Rajendran

Kuroda

et al. 2016

JCMT

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Aim:The aim of the study is to investigate the impact of the cytochrome P450 2E1, which is the most efficient CYP450 family member in generating reactive oxygen species (ROS), on cellular energy metabolism of breast cancer cells and therefore the effects of CYP2E1 on breast carcinogenesis. Methods: The estrogen receptor positive MCF-7 and the triple negative MDA-MB-231 breast cancer cells were used as experimental system to estimate ROS generation in these cells overexpressing CYP2E1 and treated with the glycolytic inhibitors 3-bromopyruvate or 2-deoxyglucose in the presence or absence of the CYP2E1 inhibitor chlormethiazole. Adenosine triphosphate (ATP) assay was used to measure ATP production and lactate assay to quantify the efflux of lactic acid in breast cancer cells treated with the CYP2E1 inhibitor chlormethiazole, the mitochondrial membrane potential and cell viability assays were employed to assess the pathway of cellular energy production and cellular death respectively after treatment of MCF-7 and MDA-MB-231 with the CYP2E1 activator acetaminophen or the CYP2E1 inhibitor chlormethiazole. Results:The results indicated increased ROS generation in breast cancer cells overexpressing CYP2E1. ROS generation was differentially regulated in breast cancer cells upon treatment with the CYP2E1 inhibitor chlormethiazole. Chlormethiazole treated MCF-7 cells exhibited reduced lactate efflux implying that CYP2E1 directly or indirectly regulates the glycolytic rate in these cells. Furthermore the mitochondrial membrane potential of both MCF-7 and MDA-MB-231 cells was differentially affected by the CYP2E1 activator acetaminophen versus the CYP2E1 inhibitor chlormethiazole providing additional support for the involvement of CYP2E1 in energy metabolic pathways in breast cancer. Conclusion: Results presented in this study provide evidence to suggest that CYP2E1 regulates cellular energy metabolism of breast cancer cells in a manner dependent on cell type and potentially on the clinical staging of the disease therefore CYP2E1 is a possible breast cancer biomarker.

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“…Moreover, the expression and activity of CYP3A4, the primary drug-metabolizing enzyme found in liver and intestine, is rapidly and dramatically repressed in response to acute inflammatory states (24). Because PXR is a master regulator of druginducible transcription of the CYP3A4 gene, there is a high level of interest in understanding the potential role of this transcription factor in mediating transcriptional suppression during these specific pathological conditions.…”

Section: Discussionmentioning

confidence: 99%

Cyclic AMP-dependent Protein Kinase Signaling Modulates Pregnane x Receptor Activity in a Species-specific Manner

Lichti-Kaiser

Staudinger

2009

Journal of Biological Chemistry

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Pregnane x receptor is a ligand-activated transcription factor that regulates drug-inducible expression of several key cytochrome P450 enzymes and drug transporter proteins in liver and intestine in a species-specific manner. Activation of this receptor modulates several key biochemical pathways, including gluconeogenesis, ␤-oxidation of fatty acids, fatty acid uptake, cholesterol homeostasis, and lipogenesis. It is of current interest to determine whether the interaction between pregnane x receptor and these key biochemical pathways is evolutionarily conserved. We show here that activation of the cyclic AMP-dependent protein kinase signaling pathway synergizes with pregnane x receptor-mediated gene activation in mouse hepatocytes. Conversely, cyclic AMP-dependent protein kinase signaling has a repressive effect upon pregnane x receptor-mediated gene activation in rat and human hepatocytes. We show that the human pregnane x receptor protein can serve as an effective substrate for catalytically active cyclic AMP-dependent protein kinase in vitro. Metabolic labeling of the protein in vivo indicates that human pregnane x receptor exists as a phosphoprotein and that activation of cyclic AMP-dependent protein kinase signaling modulates the phosphorylation status of pregnane x receptor. Activation of cyclic AMP-dependent protein kinase signaling also modulates the interactions of pregnane x receptor with protein cofactors. Our results define the species-specific impact of cyclic AMP-dependent protein kinase signaling on pregnane x receptor and provide a molecular explanation of cyclic AMP-dependent protein kinase-mediated repression of human pregnane x receptor activity. Taken together, our results identify a novel mode of regulation of pregnane x receptor activity and highlight prominent functional differences in the process across species.

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Regulation of Drug-Metabolizing Enzymes and Transporters in Inflammation

Cited by 403 publications

References 143 publications

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

Downregulation of drug transport and metabolism in mice bearing extra-hepatic malignancies

Oxidative stress and breast cancer biomarkers: the case of the cytochrome P450 2E1

Cyclic AMP-dependent Protein Kinase Signaling Modulates Pregnane x Receptor Activity in a Species-specific Manner

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