Toll-like Receptor-4 Regulation of Hepatic Cyp3a11 Metabolism in a Mouse Model of LPS-induced CNS Inflammation

Central nervous system (CNS) infection and inflammation severely reduce the capacity of cytochrome P-450 metabolism in the liver. We developed a mouse model to examine the effects of CNS inflammation on hepatic cytochrome P-450 metabolism. FVB, C57BL/6, and C3H/HeouJ mice were given Escherichia coli LPS (2.5 μg) by intracerebroventricular (ICV) injection. The CNS inflammatory response was confirmed by the elevation of TNF-α and/or IL-1β proteins in the brain. In all mouse strains, LPS produced a 60–70% loss in hepatic Cyp3a11 expression and activity compared with saline-injected controls. Adrenalectomy did not prevent the loss in Cyp3a11 expression or activity, thereby precluding the involvement of the hypothalamic-adrenal-pituitary axis. Endotoxin was detectable (1–10 ng/ml) in serum between 15 and 120 min after ICV dosing of 2.5 μg LPS. Peripheral administration of 2.5 μg LPS by intraperitoneal injection produced similar serum endotoxin levels and a similar loss (60%) in Cyp3a11 expression and activity in the liver. The loss of Cyp3a11 in response to centrally or peripherally administered LPS could not be evoked in Toll-like receptor-4 (TLR4)-mutant (C3H/ HeJ) mice, indicating that TLR4 signaling pathways are directly involved in the enzyme loss. In summary, we conclude that LPS is transferred from the brain to the circulation in significant quantities in a model of CNS infection or inflammation. Subsequently, LPS that has reached the circulation stimulates a TLR4-dependent mechanism in the periphery, evoking a reduction in Cyp3a11 expression and metabolism in the liver

COVID-19 Vaccines and the Virus: Impact on Drug Metabolism and Pharmacokinetics

This article reports on an American Society of Pharmacology and Therapeutics, Division of Drug Metabolism and Disposition symposium held at Experimental Biology on April 2nd, 2022, in Philadelphia. As of July 2022, over 500 million people have been infected with SARS-CoV-2 (the virus causing COVID-19) and over 12,000,000,000 vaccine doses have been administered. Clinically significant interactions between viral infections and hepatic drug metabolism were first recognized over 40 years ago during a cluster of pediatric theophylline toxicity cases attributed to reduced hepatic drug metabolism amidst an influenza B outbreak. Today, a substantive body of research supports that the activated innate immune response generally decreases hepatic cytochrome P450 (CYP) activity. The interactions extend to drug transporters and other organs and have the potential to impact drug absorption, distribution, metabolism, and excretion (ADME). Based on this knowledge, altered ADME is predicted with SARS-CoV-2 infection or vaccination. The report begins with a clinical case exploring the possibility of SARS-CoV-2 vaccination increasing clozapine levels. This is followed by discussions of how SARS-CoV-2 infection or vaccines alter the metabolism and disposition of complex drugs, such as nanoparticles and biologics and small molecule therapies. The review concludes with a discussion of the effects of viral infections on placental amino acid transport and their potential to impact fetal development. The session improved our understanding of the impact of emerging viral infections and vaccine technologies on drug metabolism and disposition, which will help mitigate drug toxicity and improve drug and vaccine safety and effectiveness. Significance Statement Altered pharmacokinetics of small molecule and complex molecule drugs and fetal brain distribution of amino acids following SARS-CoV-2 infection or immunization are possible. The proposed mechanisms involve decreased liver CYP metabolism of small molecules, enhanced innate immune system metabolism of complex molecules and altered placental and fetal blood-brain barrier amino acid transport, respectively. Future research is needed to understand the effects of these interactions on adverse drug responses, drug and vaccine safety and effectiveness and fetal neurodevelopment

The Anticancer Activity and Mechanisms of Action of Jadomycins in Multidrug Resistant Human Breast Cancer Cells

Breast cancer is the most common cancer in women, and approximately one third of all breast cancers will ultimately metastasize. Metastatic breast cancer is classified as an incurable disease. The development of multidrug resistance (MDR) is largely responsible for the difficulty associated with its treatment. Jadomycins are natural products biosynthesized by the bacteria Streptomyces venezuelae International Streptomyces Project (ISP) 5230, which have anticancer activity but poorly defined mechanisms of action. Preliminary research in our laboratory showed jadomycins retain their cytotoxic potency in MDR-MCF7 breast cancer cells that overexpress certain ATP-binding cassette (ABC) drug efflux transporters. My research goal was to more completely characterize jadomycin cytotoxicity profiles and pharmacological mechanisms to better understand their potential applications in the treatment of MDR breast cancer. First I show multiple jadomycin analogues retain their cytotoxic potency in ABCB1, ABCC1, or ABCG2-overexpressing MCF7 and ABCB1-overexpressing MDA-MB-231 versus control MCF7 and MDA-MB-231 breast cancer cells. Inhibitors of ABCB1, ABCC1, and ABCG2 minimally affect jadomycin cytotoxicity, suggesting jadomycins are poor ABC transporter substrates. I then show jadomycins have multiple cytotoxicity mechanisms that are influenced by breast cancer cell type. Jadomycins increase intracellular reactive oxygen species (ROS) in MCF7 and MDA-MB-231 cells. In MCF7 cells, inhibition of the antioxidant thioredoxin reductase with auranofin potentiates jadomycin cytotoxicity. Conversely, neutralization of ROS with the antioxidant N-acetylcysteine decreases jadomycin potency, but not efficacy, evidencing a ROS-independent cytotoxicity mechanism. In MDA-MB-231 cells, jadomycins cause DNA double strand breaks and apoptosis. These effects are not blocked by ROS neutralization or enhanced by antioxidant inhibition, further evidencing ROS-independent mechanisms of cytotoxicity. Additional assays show that ROS-independent mechanisms include aurora B kinase inhibition and type II topoisomerase inhibition, which can lead to DNA double strand breaks and apoptosis. These cytotoxicity mechanisms are preserved in the ABC-transporter overexpressing MCF7 and MDA-MB-231 cells, thus helping explain how jadomycins remain effective in these cells. My research is the first to detail the polypharmacology of jadomycins’ anticancer activity. Additionally, I describe the promising jadomycin activity against ABC-transporter overexpressing MDR breast cancer cells, supporting further research into how these natural products may be used as MDR metastatic breast cancer treatments

ZATT, TDP2, and SUMO2: breaking the tie that binds TOP2 to DNA

Invited Editorial Article. First paragraph: "Type II topoisomerase (TOP2) poisons are widely used chemotherapeutics that work by disrupting the cycle of TOP2-DNA interactions that are required for DNA synthesis, gene expression, and the maintenance of genome integrity. Schellenberg et al.’s recent Science paper, entitled “ZATT (ZNF451)-mediated resolution of topoisomerase 2 DNA protein cross-links” provides a major advancement in the understanding of the mechanisms that regulate TOP2-DNA interactions, and how they can inhibit the anticancer effects of TOP2 poisons. Through these new insights, promising new therapeutic targets have been identified.

Escobar and Sitar 1995, 1996) contribute to the THE

ABSTRACT Amantadine transport into renal proximal and distal tubules is bicarbonate dependent. In the present study, we addressed the effects of bicarbonate on renal clearance and urinary excretion of amantadine. Renal clearance of kynurenic acid was also studied to determine whether bicarbonate effects are specific for organic base transport by the kidney. 3 H]kynurenic acid, blood gases, and pH. Amantadine and kynurenic acid were excreted by the kidneys, and both compounds underwent renal tubular secretion. Amantadine metabolism occurred, and one metabolite was detected in the urine. In the bicarbonate-treated rats, the total amount of amantadine excreted in the urine was decreased, whereas the amount of metabolite recovered was similar in both groups. Bicarbonate treatment caused a sustained increase in blood bicarbonate levels, a mild increase in blood pH, and a decrease in amantadine renal clearance and in the amantadine/creatinine clearance ratio. Only a transient decrease in the renal clearance of kynurenic acid and the kynurenic acid/creatinine clearance ratio was observed. This study demonstrates that short-term changes in bicarbonate concentration may have significant effects on renal organic cation elimination. Coupled with our previous in vitro demonstration of bicarbonate-dependent organic cation transport, the present study suggests that bicarbonate inhibition of renal tubule organic cation secretion may explain the previous observation that bicarbonate dosing decreases amantadine excretion by the kidney. Organic cation transport plays an important role in the renal tubule secretion and the elimination of many exogenous cationic compounds from the body In the study b

COVID-19 pathophysiology and pharmacology: What do we know and how did Canadians respond? A review of Health Canada authorized clinical vaccine and drug trials.

Coronavirus disease 2019 (COVID-19) has resulted in the death of over 18000 Canadians and has impacted the lives of all Canadians. Many Canadian research groups have expanded their research programs to include COVID-19. Over the past year, our knowledge of this novel disease has grown and has led to the initiation of a number of clinical vaccine and drug trials for the prevention and treatment of COVID-19. Here, we review SARS-CoV-2 (the coronavirus that causes COVID-19) and the natural history of COVID-19, including a timeline of disease progression after SARS-CoV-2 exposure. We also review the pathophysiological effects of COVID-19 on the organ systems that have been implicated in the disease, including the lungs, upper respiratory tract, immune system, central nervous system, cardiovascular system, gastrointestinal organs, the liver, and the kidneys. Then we review general therapeutics strategies that are being applied and investigated for the prevention or treatment of COVID-19, including vaccines, antivirals, immune system enhancers, pulmonary supportive agents, immunosuppressants/anti-inflammatories, and cardiovascular system regulators. Finally, we provide an overview of all current Health Canada authorized clinical drug and vaccine trials for the prevention or treatment of COVID-19.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

More Than an Adipokine: The Complex Roles of Chemerin Signaling in Cancer

Chemerin is widely recognized as an adipokine, with diverse biological roles in cellular differentiation and metabolism, as well as a leukocyte chemoattractant. Research investigating the role of chemerin in the obesity–cancer relationship has provided evidence both for pro- and anti-cancer effects. The tumor-promoting effects of chemerin primarily involve direct effects on migration, invasion, and metastasis as well as growth and proliferation of cancer cells. Chemerin can also promote tumor growth via the recruitment of tumor-supporting mesenchymal stromal cells and stimulation of angiogenesis pathways in endothelial cells. In contrast, the majority of evidence supports that the tumor-suppressing effects of chemerin are immune-mediated and result in a shift from immunosuppressive to immunogenic cell populations within the tumor microenvironment. Systemic chemerin and chemerin produced within the tumor microenvironment may contribute to these effects via signaling through CMKLR1 (chemerin1), GPR1 (chemerin2), and CCLR2 on target cells. As such, inhibition or activation of chemerin signaling could be beneficial as a therapeutic approach depending on the type of cancer. Additional studies are required to determine if obesity influences cancer initiation or progression through increased adipose tissue production of chemerin and/or altered chemerin processing that leads to changes in chemerin signaling in the tumor microenvironment

CMKLR1 activation ex vivo does not increase proportionally to serum total chemerin in obese humans

Prochemerin is the inactive precursor of the adipokine chemerin. Proteolytic processing is obligatory for the conversion of prochemerin into active chemerin and subsequent regulation of cellular processes via the chemokine-like receptor 1 (CMKLR1). Elevated plasma or serum chemerin concentrations and differential processing of prochemerin have been reported in obese humans. The impact of these changes on CMKLR1 signalling in humans is unknown. The objective of this pilot study was to develop a cellular bioassay to measure CMKLR1 activation by chemerin present in human serum and to characterise how obesity modifies serum activation of CMKLR1 under fasted and fed conditions. Blood samples were collected from control (N = 4, BMI 20–25) and obese (N = 4, BMI >30) female subjects after an overnight fast (n = 2) and at regular intervals (n = 7) following consumption of breakfast over a period of 6 h. A cellular CMKLR1-luminescent reporter assay and a pan-chemerin ELISA were used to determine CMKLR1 activation and total chemerin concentrations, respectively. Serum total chemerin concentration (averaged across all samples) was higher in obese vs control subjects (17.9 ± 1.8 vs 10.9 ± 0.5 nM, P < 0.05), but serum activation of CMKLR1 was similar in both groups. The CMKLR1 activation/total chemerin ratio was lower in obese vs control subjects (0.33 ± 0.04 vs 0.58 ± 0.05, P < 0.05). After breakfast, serum total chemerin or CMKLR1 activation did not differ from baseline values. In conclusion, the unexpected observation that obese serum activation of CMKLR1 did not match increased total chemerin concentrations suggests impaired processing to and/or enhanced degradation of active chemerin in serum of obese humans