Pharmacology Research and Perspectives

Drug‐induced toxicity is a key issue for public health because some side effects can be severe and life‐threatening. These adverse effects can also be a major concern for the pharmaceutical companies since significant toxicity can lead to the interruption of clinical trials, or the withdrawal of the incriminated drugs from the market. Recent studies suggested that endoplasmic reticulum (ER) stress could be an important event involved in drug liability, in addition to other key mechanisms such as mitochondrial dysfunction and oxidative stress. Indeed, drug‐induced ER stress could lead to several deleterious effects within cells and tissues including accumulation of lipids, cell death, cytolysis, and inflammation. After recalling important information regarding drug‐induced adverse reactions and ER stress in diverse pathophysiological situations, this review summarizes the main data pertaining to drug‐induced ER stress and its potential involvement in different adverse effects. Drugs presented in this review are for instance acetaminophen (APAP), arsenic trioxide and other anticancer drugs, diclofenac, and different antiretroviral compounds. We also included data on tunicamycin (an antibiotic not used in human medicine because of its toxicity) and thapsigargin (a toxic compound of the Mediterranean plant Thapsia garganica) since both molecules are commonly used as prototypical toxins to induce ER stress in cellular and animal models.

The aim of the study was to investigate the in vitro and in vivo pharmacological profile of cebranopadol, a novel agonist for opioid and nociceptin/orphanin FQ (N/OFQ) receptors (NOP). In vitro cebranopadol was assayed in calcium mobilization studies in cells coexpressing NOP or opioid receptors and chimeric G‐proteins and in a bioluminescence resonance energy transfer (BRET) assay for studying receptor interaction with G‐protein and β‐arrestin 2. The mouse tail withdrawal and formalin tests were used for investigating cebranopadol antinociceptive properties. In calcium mobilization studies cebranopadol showed the following rank order of potency NOP = mu > kappa ≥ delta. In BRET studies, cebranopadol promoted NOP and mu receptors interaction with G‐protein with similar high potency and efficacy. However, cebranopadol did not stimulated NOP–β‐arrestin 2 interactions and displayed reduced potency at mu/β‐arrestin 2. In vivo, cebranopadol exhibits highly potent and extremely long‐lasting antinociceptive effects. The effects of cebranopadol in the tail withdrawal assay were sensitive to both SB‐612111 and naloxone. Collectively the present results confirm and extend previous finding demonstrating that cebranopadol, by acting as mixed NOP/opioid receptor agonist, elicits robust analgesic effects in different pain models.

More than ten million patients worldwide have been diagnosed with coronavirus disease 19 (COVID‐19) to date (WHO situation report, 1st July 2020). There is no vaccine to prevent infection with the causative organism, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), nor a cure. In the struggle to devise potentially useful therapeutics in record time, the repurposing of existing compounds is a key route of action. In this hypothesis paper, we argue that the bisbenzylisoquinoline and calcium channel blocker tetrandrine, originally extracted from the plant Stephania tetrandra and utilized in traditional Chinese medicine, may have potential in the treatment of COVID‐19 and should be further investigated. We collate and review evidence for tetrandrine's putative mechanism of action in viral infection, specifically its recently discovered antagonism of the two‐pore channel 2 (TPC2). While tetrandrine's particular history of use provides a very limited pharmacological dataset, there is a suggestion from the available evidence that it could be effective at doses used in clinical practice. We suggest that further research to investigate this possibility should be conducted.

The hypoxia‐sensing transcriptional factor HIF1α is implicated in a variety of hepato‐pathological conditions; however, the contribution of hepatocyte‐derived HIF1α during progression of alcoholic liver injury is still controversial. HIF1α induces a variety of genes including those involved in apoptosis via p53 activation. Increased hepatocyte apoptosis is critical for progression of liver inflammation, stellate cell activation, and fibrosis. Using hepatocyte‐specific HIF1α‐deficient mice (ΔHepHIF1α^−/−), here we investigated the contribution of HIF1α to ethanol‐induced hepatocyte apoptosis and its role in amplification of fibrosis after carbon tetrachloride (CCl₄) exposure. Moderate ethanol feeding (11% of kcal) induced accumulation of hypoxia‐sensitive pimonidazole adducts and HIF1α expression in the liver within 4 days of ethanol feeding. Chronic CCl₄ treatment increased M30‐positive cells, a marker of hepatocyte apoptosis in pair‐fed control mice. Concomitant ethanol feeding (11% of kcal) amplified CCl₄‐induced hepatocyte apoptosis in livers of wild‐type mice, associated with elevated p53^K386 acetylation, PUMA expression, and Ly6c⁺ cell infiltration. Subsequent to increased apoptosis, ethanol‐enhanced induction of profibrotic markers, including stellate cell activation, collagen 1 expression, and extracellular matrix deposition following CCl₄ exposure. Ethanol‐induced exacerbation of hepatocyte apoptosis, p53^K386 acetylation, and PUMA expression following CCl₄ exposure was attenuated in livers of ΔHepHIF1α^−/− mice. This protection was also associated with a reduction in Ly6c⁺ cell infiltration and decreased fibrosis in livers of ΔHepHIF1α^−/− mice. In summary, these results indicate that moderate ethanol exposure leads to hypoxia/HIF1α‐mediated signaling in hepatocytes and induction of p53‐dependent apoptosis of hepatocytes, resulting in increased hepatic fibrosis during chronic CCl₄ exposure.

We propose a new hypothesis that the established drug pentoxifylline deserves attention as a potential repurposed therapeutic for COVID‐19. Pentoxifylline is an immunomodulator with anti‐inflammatory properties. It is a nonselective phosphodiesterase inhibitor and through Adenosine A2A Receptor‐mediated pathways reduces tumor necrosis factor alpha, interleukin 1, interleukin 6, and interferon gamma and may act to reduce tissue damage during the cytokine storm host response to SARS‐CoV‐2 infection. This agent has been used clinically for many years and has a favorable profile of safety and tolerability. Pre‐clinical data support pentoxifylline as effective in cytokine‐driven lung damage. Clinical studies of pentoxifylline in radiation and cytokine‐induced lung damage in humans are positive and consistent with anti‐inflammatory efficacy. Pentoxifylline is a readily available, off‐patent and inexpensive drug, suitable for large‐scale use including in resource‐limited countries. Current trials of therapeutics are largely focused on the inhibition of viral processes. We advocate urgent randomized trials of pentoxifylline for COVID‐19 as a complementary approach to target the host responses.

Cytochrome P450 (CYP) 3A4 is a membrane protein that catalyzes hydroxylation of endogenous and exogenous substrates. Protein–protein interaction is a crucial factor that regulates the function of enzymes. However, protein–protein interactions involving human CYPs have not been fully understood. In this study, extensive protein–protein interactions involving CYP3A4 were determined by a shotgun analysis of immunoprecipitate utilizing anti‐CYP3A4 antibody. Our shotgun analysis revealed that 149 proteins were immunoprecipitated with anti‐CYP3A4 antibody in human liver microsomes. We further determined that 51 proteins of 149 proteins were specifically immunoprecipitated with the anti‐CYP3A4 antibody. Our analysis demonstrated that other CYP isoforms are interacting with CYP3A4, which is in agreement with previous findings. Based on our current and previous findings, we propose that drug‐metabolizing enzymes such as CYP3A4 and UDP‐glucuronosyltransferase 2B7 form a metabolosome, which is a functional unit of metabolism consisting of multiple metabolism‐related proteins.