Clinical guidance for cannabidiol-associated hepatotoxicity: A narrative review.

There is increasing evidence that cannabidiol (CBD) use is associated with clinically significant liver enzyme (LE) elevations and drug-induced liver injury (DILI). The proportion of LE elevations and DILI events reported in the literature meet the Council for International Organizations of Medical Sciences' (CIOMS) classification of a common adverse drug reaction. However, these potential adverse events are unknown to many clinicians and may be overlooked. The increasing use of CBD for both medical and non-medical use necessitates clear direction in the diagnosis and management of CBD-associated hepatotoxicity. To our knowledge, no such clinical guidance currently exists. For people presenting with elevated LEs, CBD use should be screened for and be considered in the differential diagnosis. This narrative review will provide clinicians with guidance in the prevention, detection, and management of CBD-related hepatotoxicity.

Inhibitory Effects of Flavonoids on Organic Cation Transporter 1: Implications for Food/herb-drug Interactions and Hepatoprotective Effects.

Organic cation transporter 1 (OCT1, gene symbol: SLC22A1) is mainly responsible for the hepatic uptake of various cationic drugs, closely associated with drug-induced liver injury (DILI). Screening and identifying potent OCT1 inhibitors with little toxicity in natural products is of great value in alleviating OCT1-mediated liver injury. Flavonoids, a group of polyphenols commonly found in foodstuffs and herbal products, have been reported to cause transporter-mediated food/herb-drug interactions (FDIs). Our objective was to investigate potential inhibitors of OCT1 from 96 flavonoids, evaluate the hepatoprotective effects on retrorsine-induced liver injury, and clarify the structure-activity relationships of flavonoids with OCT1. Thirteen flavonoids exhibited significant inhibition (>50%) on OCT1 in OCT1-HEK293 cells. Among them, the five strongest flavonoid inhibitors (IC50<10µM), including α-naphthoflavone, apigenin, 6-hydroxyflavone, luteolin, and isosilybin markedly decreased oxaliplatin-induced cytotoxicity. In retrorsine-induced liver injury models, they also reduced alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to different levels, the best of which was 6-hydroxyflavone. The pharmacophore model clarified that hydrogen bond acceptors at the 4,8,5' position might play a vital role in the inhibitory effect of flavonoids on OCT1. Taken together, our findings would pave the way to predicting the potential risks of flavonoid-related FDIs in humans and optimizing flavonoid structure to alleviate OCT1-mediated liver injury.

Inhibition of 15-prostaglandin dehydrogenase attenuates acetaminophen-induced liver injury via suppression of apoptosis in liver endothelial cells.

Hepatic microvascular disruption caused by injury to liver sinusoidal endothelial cells (LSECs) is an aggravating factor for drug-induced liver injury (DILI). It is suggested that prostaglandin E2 (PGE2) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE2, a metabolite of PGE2 produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE2 receptors, suppresses inflammatory acute liver injury as a ligand of peroxisome proliferator-activated receptor γ. In this study, we aimed to understand whether 15-PGDH activity is essential for preventing DILI by suppressing hepatic microvascular disruption in a mouse model of acetaminophen (APAP)-induced liver injury. To inhibit 15-PGDH activity prior to APAP-induced LSEC injury, we administered the 15-PGDH inhibitor, SW033291, 1 h before and 3 h after APAP treatment. We observed that LSEC injury preceded hepatocellular injury in APAP administered mice. Hepatic endogenous PGE2 levels did not increase up till the initiation of LSEC injury but rather increased after hepatocellular injury. Moreover, hepatic 15-PGDH activity was downregulated in APAP-induced liver injury. The inhibition of 15-PGDH attenuated LSEC injury and subsequently hepatic injury by inhibiting apoptosis in APAP administered mice. Our in vitro studies also suggested that PGE2 inhibited APAP-induced apoptosis via the EP4/PI3K pathway in endothelial cells. Therefore, a decrease in 15-PGDH activity would be beneficial for preventing APAP-induced liver injury by attenuating LSEC injury.

Drug-induced liver injury related to gene therapy: A new challenge to be managed.

Gene therapy is being successfully developed for the treatment of several genetic disorders. Various methods of gene transfer have been developed to enable the production of the deficient enzyme or protein. One of the most important is adeno-associated virus vectors, which have been shown to be viable for use in in vivo gene therapy. Several gene therapies have already been approved. They are also promising for acquired diseases. Important examples include gene therapy for haemophilia A and B, X-linked myotubular myopathy, spinal muscular atrophy and several liver diseases such as Criggler-Najjar disease, alpha-1 antitrypsin deficiency and Fabry disease. However, the introduction of a foreign compound into hepatocytes leads to hepatic reactions with heterogeneous phenotypic expression and a wide spectrum of severity, ranging from mild transaminase elevation to acute liver failure. Several mechanisms appear to be involved in liver injury, including an immune response, but also direct toxicity depending on the method of gene transfer. As a result, the incidence, expression and severity of liver injury vary from indication to indication and from patient to patient. Patients treated for haemophilia A are more prone to transaminase elevation than those treated for haemophilia B. Corticosteroids are successfully used to correct liver reactions but also to prevent degradation of the transferred gene and loss of therapeutic activity. The aim of this review is to describe the risk of liver injury according to the indication for gene therapy and the short- and long-term management currently proposed to prevent or correct liver reactions in clinical practice.

A Case of Severe Thrombocytopenia, Aseptic Meningitis, and Hepatitis Caused by Trimethoprim-Sulfamethoxazole: A Triple Threat.

Trimethoprim-sulfamethoxazole (TMP-SMX), a widely used antibiotic, is associated with both predictable dose-dependent side effects and rare, idiosyncratic adverse reactions. Here, we report the case of a previously healthy, non-G6PD-deficient, 27-year-old male who developed three idiosyncratic reactions: severe thrombocytopenia, aseptic meningitis, and hepatitis concurrently following TMP-SMX administration. The Naranjo adverse reaction probability score was 7, implying TMP-SMX as the probable cause of the clinical presentation. After a comprehensive workup to rule out alternate etiologies, we have established TMP-SMX as the culprit. Our case highlights the importance of early recognition of TMP-SMX-induced rare adverse events for appropriate management to mitigate long-term sequelae and ensure favorable patient outcomes.

Caffeine-Induced Psychosis: A Case Report and Review of Literature.

A 51-year-old female, with no previous history of psychosis, presented to the Emergency Department with an acute psychotic episode in the context of excess caffeine consumption. Caffeine is an adenosine antagonist. An antagonist of adenosine can lead to the release of dopamine into the synaptic cleft, which can induce psychotic symptoms in vulnerable individuals. The patient had consumed caffeine in the form of up to eight energy drinks daily. She experienced persecutory delusions alongside auditory and visual hallucinations. She did not have a history of psychotic disorder but did have a history of generalized anxiety disorder. Upon cessation of caffeine, her symptoms resolved within five days. She remained caffeine-free and symptom-free 18 months later when reviewed in the community. This case highlights the potential psychiatric consequences of excessive caffeine consumption and identifies the need to screen for excessive consumption of caffeine in individuals presenting with new psychotic symptoms or worsening of pre-existing psychotic symptoms.

Internalization of extracellular vesicles of cancer patients by peripheral blood mononuclear cells during polychemotherapy: connection with neurotoxicity.

Extracellular vesicles (EVs), exhibiting their functional activity after internalization by recipient cells, are involved in the pathogenesis of drug-induced polyneuropathy (DIPN), a common complication of antitumor therapy. In this work, the internalization of EVs obtained from colorectal cancer patients undergoing polychemotherapy and its relationship with neurotoxicity were assessed using a model system of mononuclear leukocytes. Circulating EVs were isolated from 8 colorectal cancer patients who received antitumor therapy according to the FOLFOX or XELOX regimens before the start of chemotherapy (point 1) and after 3-4 courses (point 2). Mononuclear leukocytes of a healthy donor served as a cellular model system for EV internalization in vitro. EV internalization was assessed using fluorescence microscopy. It was shown that internalization of EVs obtained from colorectal cancer patients with high neurotoxicity was higher than in the group with low neurotoxicity. The ability of CD11b-positive (CD11b⁺) and CD11b-negative (CD11b⁻) mononuclear leukocytes of a healthy donor to internalize EVs obtained from patients before and after chemotherapy did not reveal significant differences. A direct relationship was found between the relative number of CD11b⁻ cells with internalized EVs and the integral index of neurotoxicity according to the NRS scale at the peak of its manifestation (point 2) (r=0.675, p.

Tofacitinib-Induced Acute Pancreatitis in a Patient with Rheumatoid Arthritis: A Case Report and Review of the Literature.

BACKGROUND: Acute Pancreatitis (AP) is an uncommon complication that rarely occurs during Rheumatoid Arthritis (RA). Among the varied etiologies of AP, Drug-induced Pancreatitis (DIP) remains a rare entity and a rather challenging condition. A large panel of drugs have been reported to cause pancreatitis; however, there are no cases of tofacitinib-induced pancreatitis reported in the literature. CASE PRESENTATION: We have, herein, reported the case of a Tunisian 58-year-old woman with a four-year history of RA who experienced two episodes of AP; the first one occurred on the second day of a 3-day series of methylprednisolone intravenous injections, and the second episode occurred on the sixth-day of tofacitinib administration. Each time, she presented acute abdominal pain with characteristic radiation to the back. Symptoms resolved spontaneously once the suspected drug was discontinued. In the event of a negative investigation, including abdominal ultrasonography and magnetic resonance imaging, and assessment of albumin, calcemia, triglyceridemia, serum ferritin, and IgG4 levels, DIP was the most likely diagnosis. CONCLUSION: Although DIP is still a rare condition, it remains serious with an increased risk of mortality. We intended to alert clinicians that in addition to the known side effects of tofacitinib, pancreatitis may be induced by this drug, especially in predisposed patients.

Novel reduced heteropolyacid nanoparticles for effective treatment of drug-induced liver injury by manipulating reactive oxygen and nitrogen species and inflammatory signals.

With the rapid advancements in biomedicine, the use of clinical drugs has surged sharply. However, potential hepatotoxicity limits drug exploitation and widespread usage, posing serious threats to patient health. Hepatotoxic drugs disrupt liver enzyme levels and cause refractory pathological damage, creating a challenge in the application of diverse first-line drugs. The activation and deterioration of reactive oxygen and nitrogen species (RONS) and inflammatory signals are key pathological mechanisms of drug-induced liver injury (DILI). Herein, a novel reduced heteropolyacid nanoparticle (RNP) has been developed, possessing high RONS-scavenging ability, strong anti-inflammatory activity, and excellent biosafety. These features enable it to swiftly restore the redox and immune balance of the liver. Intravenous administration of RNP effectively scavenged RONS storm, reversing liver oxidative stress and restoring normal mitochondrial membrane potential and function. Furthermore, by inhibiting c-Jun-N-terminal kinase phosphorylation, RNP facilitated the restoration of nuclear factor erythroid 2-related factor 2-mediated endogenous antioxidant signaling, ultimately rescuing the liver function and tissue morphology in acetaminophen-induced DILI mice. Crucially, the high biocompatible RNP exhibited superior efficacy in the DILI mouse model compared to the clinical antioxidant N-acetylcysteine. This targeted therapeutic approach, tailored to address the onset and progression of DILI, offers valuable new insights into controlling the condition and restoring liver structure and function.

A hemicyanine-modified upconversion nanoprobe for NIR-excited evaluating superoxide signaling in drug-induced liver injury.

BACKGROUND: Drug-induced liver injury (DILI) is the most important standard for the entrance of clinical drugs into the pharmaceutical market. The elevation of superoxide anion (O2•-) during drug metabolism can mediate apoptosis of hepatocytes and further generation of liver damage. Therefore, developing an effective imaging method for evaluating O2•- levels during DILI is of great importance. However, current reported O2•- fluorescent probes either use short excitation wavelengths or a single intensity detection system, limiting the accurate quantification of O2•- in deep tissue in vivo. RESULTS: We developed a NIR-excited ratiometric nanoprobe (CyD-UCNPs) by assembly of O2•--sensitive hemicyanine dyes (CyD) on the surface of Tm/Er-codoped upconversion nanoparticles (UCNPs) with the assistance of α-cyclodextrin, which exhibited a robust "turn-on" ratiometric sensing signal. In vitro experiments indicated that CyD-UCNPs respond well to O2•- with high selectivity. Furthermore, by taking advantage of the outstanding optical properties produced by the luminescent resonance energy transfer between the UCNPs and CyD upon the excitation of 980 nm, the ratiometric upconversion luminescence signal of CyD-UCNPs was successfully utilized to monitor the fluctuation of O2•- levels under phorbol-12-myristate-13-acetate (PMA)/cisplatin-induced oxidative stress in living cells, liver tissues, and zebrafish. More importantly, endogenous change in O2•- levels in the liver sites of mice during DILI and its prevention with L-carnitine was visualized using CyD-UCNPs. SIGNIFICANCE: This study provides a ratiometric NIR-excited imaging strategy for investigating the correlation between O2•- levels and DILI and its prevention, which is significant for early diagnosis of DILI and preclinical screening of anti-hepatotoxic drugs in vivo.

Paeoniflorin protects hepatocytes from APAP-induced damage through launching autophagy via the MAPK/mTOR signaling pathway.

BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. PURPOSE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.

Assessing Hepatotoxicity in Novel and Standard Short Regimens for Rifampicin-Resistant Tuberculosis: Insights from the TB-TRUST and TB-TRUST -plus Trials.

BACKGROUND: Efforts to shorten rifampicin-resistant tuberculosis (RR-TB) treatment have led to concerns about hepatotoxicity in shorter regimens. We evaluated hepatotoxicity in two novel regimens against the standard shorter regimen recommended by WHO. METHODS: Participants from the TB-TRUST and TB-TRUST plus trials were assigned to the WHO shorter regimen, a levofloxacin-based regimen, or a bedaquiline-based regimen. Liver function was tested bi-weekly in the first month, then monthly until treatment ended. Eligibility required receiving at least one drug dose and undergoing at least two liver function tests. RESULTS: Of 429 patients, hepatotoxicity was most prevalent in the WHO shorter group (26.7% of 169), compared to 4.7% in the levofloxacin group (172 patients), and 5.7% in the bedaquiline group (88 patients). The median peak ALT levels were 1.67 × ULN for WHO, 0.82 × ULN for levofloxacin, and 0.88 × ULN for bedaquiline groups. The incidence of drug-induced liver injury was significantly higher in the WHO group (18.3%) than in the levofloxacin (3.5%) and bedaquiline (4.6%) groups. Time to significant ALT elevation was about 2.8 months, with no differences between groups. CONCLUSIONS: Two novel regimens demonstrated lower hepatotoxicity compared to the WHO shorter regimen. Entire course management monitoring is recommended in RR-TB treatment.

Ibrutinib-Related Uveitis: A Case Series from Two Tertiary Centres in the United Kingdom.

PURPOSE: Ibrutinib is an irreversible Bruton's tyrosine kinase inhibitor that disrupts B-cell receptor signalling. It is licensed for treatment of low-grade B-cell malignancies, including chronic lymphocytic leukaemia, mantle cell lymphoma and lymphoplasmacytic lymphoma. A few case reports in the literature suggest that uveitis may be a side effect of ibrutinib treatment. A strong association between ibrutinib and uveitis is yet to be established in significant numbers. METHODS: The study is a retrospective case series, reporting cases of uveitis associated with ibrutinib from two tertiary centres in the United Kingdom: Liverpool University Hospitals NHS Foundation Trust and University Hospitals of Leicester NHS Trust. RESULTS: The study reports eight cases presenting over a four year period, with mean age of 66.8 years. Onset of uveitis was between 9 and 48 (median 14) months from commencing ibrutinib, categorising it as a Type D or delayed drug reaction. Cases included unilateral and bilateral; anterior, intermediate, posterior and panuveitis. There was an association with cystoid macular oedema or disc swelling. Severity varied from mild, to severe and vision threatening. Presenting visual acuity ranged from 6/9 to 6/60. In all eight cases, uveitis resolved after ibrutinib cessation. In two cases, reintroducing ibrutinib caused uveitis recurrence. CONCLUSION: Our case series provides evidence suggestive of a connection between ibrutinib and development of uveitis. Ibrutinib related uveitis appears to be more common than previously recognised. Ibrutinib cessation, if appropriate, appears to be the definitive management. Patients with ibrutinib-related uveitis benefit from multidisciplinary management involving communication between ophthalmologist and haemato-oncologist.

The Atypical Face of Neuroleptic Malignant Syndrome: A Case Report of Ileus and Absent Rigidity.

Neuroleptic malignant syndrome (NMS) is a rare life-threatening condition associated with the use of antipsychotic medications. This case report describes a male patient in his early 30s who presented with fever, breathlessness, and lower limb weakness, ultimately diagnosed with NMS despite the absence of muscular rigidity. On examination, he was febrile, tachycardic, and tachypneic with an oxygen saturation of 88% and elevated blood pressure. On auscultation diffuse crepitations in both lungs were revealed. Neurological assessment indicated motor strength of 3/5 in both lower limbs, without rigidity, sensory loss, or cerebellar signs. It was noted that he was on irregular atypical antipsychotic medication for the past one year. Laboratory investigations revealed leukocytosis, elevated transaminases, dyselectrolytemia, elevated creatine phosphokinase (CPK), and serum creatinine. NMS was not initially considered due to the lack of muscular rigidity. However, the patient later developed autonomic dysregulation manifestations, such as paralytic ileus. Once organic causes were excluded, NMS was diagnosed. Supportive therapy included 23 cycles of hemodialysis and colonic decompression for pseudo-obstruction. He was treated with intravenous fluids and dopamine receptor agonist medications. NMS usually presents with fever, muscular rigidity, altered mental status, and autonomic instability; yet, the absence of muscular rigidity in this patient is a distinctive and unusual feature.

A Case of Amiodarone-Induced Thyrotoxicosis Presenting With Methimazole-Induced Agranulocytosis.

Amiodarone is a class III anti-arrhythmic drug found to be effective in treating multiple life-threatening arrhythmias, including paroxysmal atrial fibrillation. Despite its effectiveness, amiodarone has been found to result in thyroid dysfunction. Amiodarone-induced thyrotoxicosis (AIT) is classified as type 1, which often develops in those with autoimmune hyperthyroid conditions, or type 2, which occurs because of destructive thyroiditis in an apparently normal thyroid. Differentiating between both types often poses a clinical and therapeutic dilemma, as AIT 1 is treated with thionamides, whereas AIT 2 requires steroids for treatment. We present a case of a patient with AIT who was treated empirically for both subtypes with methimazole and prednisone without clinical improvement. Methimazole was later stopped due to concern for agranulocytosis, and the patient was then treated with cholestyramine, metoprolol, and prednisone. Given persistent thyrotoxicosis, the decision was made to proceed with surgical intervention. The patient underwent a successful total thyroidectomy without complications. The patient's condition clinically improved post-surgery and was discharged home on post-operative day 2 in stable condition. Prednisone was tapered over two weeks, and he was started on a weight-based dose of levothyroxine. He continues to follow up in our clinic for postoperative hypothyroidism and is clinically and biochemically euthyroid.

The Atypical Presentation of Ifosfamide-Induced Renal Tubular Acidosis.

Antineoplastic agents are often associated with a wide range of side effects, caused by either direct toxicity or indirect through their metabolism. Ifosfamide is a cytotoxic, antineoplastic medication that is known to cause a direct tubular injury with an associated normal anion gap metabolic acidosis due to type 1 or type 2 renal tubular acidosis (RTA). The manifestations and approach to its diagnosis have been well established. However, we present a case in which a patient presented with acute symptomatic hypokalemia in the setting of ongoing ifosfamide use for metastatic osteosarcoma but without the typical laboratory findings. The clinical- and laboratory-driven diagnosis of suspected type 3 renal tubular acidosis involving proximal and distal segments is suggested by this case report.

Impact of social vulnerability index on severity of obstructive sleep apnea: Insights from drug-induced sleep endoscopy.

OBJECTIVES: To examine the association between neighborhood-level social vulnerability on the severity of obstructive sleep apnea (OSA) in patients undergoing drug-induced sleep endoscopy (DISE). STUDY DESIGN: Single center retrospective cohort study. METHODS: We conducted a retrospective chart review of patients >18 years of age that underwent DISE from July 2016 to July 2022. Patient addresses were geocoded with geographic information systems, and spatial overlays were used to assign census-tract level social vulnerability index (SVI) scores in the four sub-themes: Socioeconomic (theme 1), Household Composition/Disability (theme 2), Minority Status/Language (theme 3), and Housing/Transportation (theme 4). RESULTS: The study included 165 patients (61.2 years ± 11.6; 31.0 BMI ± 6.1, 102 male, 63 female). Mild OSA was present in13 patients; 55 patients had moderate OSA; and 97 patients had severe OSA. A higher SVI value in minority status and language, and a higher BMI both predicted an increased Apnea Hypopnea Index (AHI) (p = 0.042, and <0.001, respectively) in the multivariate model; whereas, race, age, gender, or the other three SVI sub-theme values were not predictive. CONCLUSION: Adults residing in areas of greater social vulnerability - specifically a larger minority presence or English as a second language - and patients who are obese are more likely to have more severe OSA. There was no correlation, however, between obesity and residence in an area of high SVI. These results suggest that both neighborhood conditions and obesity are associated with OSA severity. This elevated risk has potential implications for diagnostic testing, clinic follow-ups, screening, and treatment plans for adults residing in disenfranchised neighborhoods. LEVEL OF EVIDENCE: IV.

Airway and Airway Obstruction Site Segmentation Study Using U-Net with Drug-Induced Sleep Endoscopy Images.

Obstructive sleep apnea is characterized by a decrease or cessation of breathing due to repetitive closure of the upper airway during sleep, leading to a decrease in blood oxygen saturation. In this study, employing a U-Net model, we utilized drug-induced sleep endoscopy images to segment the major causes of airway obstruction, including the epiglottis, oropharynx lateral walls, and tongue base. The evaluation metrics included sensitivity, specificity, accuracy, and Dice score, with airway sensitivity at 0.93 (± 0.06), specificity at 0.96 (± 0.01), accuracy at 0.95 (± 0.01), and Dice score at 0.84 (± 0.03), indicating overall high performance. The results indicate the potential for artificial intelligence (AI)-driven automatic interpretation of sleep disorder diagnosis, with implications for standardizing medical procedures and improving healthcare services. The study suggests that advancements in AI technology hold promise for enhancing diagnostic accuracy and treatment efficacy in sleep and respiratory disorders, fostering competitiveness in the medical AI market.

Uncovering the mechanism of troglitazone-mediated idiosyncratic drug-induced liver injury with individual-centric models.

Idiosyncratic drug-induced liver injury is a rare and unpredictable event. Deciphering its initiating-mechanism is a hard task as its occurrence is individual dependent. Thus, studies that utilize models that are not individual-centric might drive to a general mechanistic conclusion that is not necessarily true. Here, we use the individual-centric spheroid model to analyze the initiating-mechanism of troglitazone-mediated iDILI risk. Individual-centric spheroid models were generated using a proprietary cell educating technology. These educated spheroids contain hepatocytes, hepatic stellate cells, activated monocyte-derived macrophages, and dendritic cells under physiological conditions. We show that phases 1 and 2 drug-metabolizing enzymes were induced in an individual-dependent manner. However, we did not observe any association of DEMs induction and troglitazone (TGZ)-mediated iDILI risk. We analyzed TGZ-mediated iDILI and found that a 44-year-old male showed iDILI risk that is associated with TGZ-mediated suppression of IL-12 expression by autologous macrophages and dendritic cells. We performed a rescue experiment and showed that treatment of spheroids from this 44-year-old male with TGZ and recombinant IL-12 suppressed iDILI risk. We confirmed the mechanism in another 31-year-old female with iDILI risk. We demonstrate here that individual-centric spheroid are versatile models that allow to predict iDILI risk and to analyze a direct effect of the drug on activated macrophages and dendritic cells to uncover the initiating-mechanism of iDILI occurrence. This model opens perspectives for a personalized strategy to mitigate iDILI risk.