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Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention

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A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 28 February 2025 | Viewed by 25247

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Dr. Anna Merwid-Ląd

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Guest Editor

Department of Pharmacology, Wroclaw Medical University, 50-367 Wrocław, Poland
Interests: pharmacology and toxicology; oxidative stress; drug-induced organ injuries; prevention of organ damages

Dr. Malgorzata Trocha

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Guest Editor

Clinical Department of Diabetology and Internal Diseases, Wroclaw Medical University, Wroclaw, Poland
Interests: medicine; ischemia/reperfusion injury; pharmacology; hypertension

Special Issue Information

Dear Colleagues,

The liver is an important organ in the organism regulating many physiological functions in the digestion process. It plays a crucial role in xenobiotics metabolism, detoxification, and clearance. Therefore, the liver is one of the main targets of drug toxicity. Many endogenous and exogenous substances are metabolized in the liver and may be harmful to this organ, causing acute or chronic liver injury.

Prescription-only medicines or over-the-counter drugs may cause liver function disturbances and liver tissue damage by a variety of mechanisms. Recently, the use of herbal formulations, sometimes from unknown sources, has increased gradually from year to year all over the world. In addition to the postulated and well-known benefits of such formulations, their liver toxicity is sometimes not well-established, which is an important field of research. Although the mechanism of drug-induced liver toxicity seems to be much better described, many newly recognized intracellular pathways are considered important in hepatotoxicity, which opens new possibilities for successful prevention and treatment.

We invite authors to submit research articles and reviews on the topic of drug-induced or herbal hepatotoxicity and the currently available methods of its prevention, as well as future perspectives.

Dr. Anna Merwid-Ląd
Dr. Malgorzata Trocha
Guest Editors

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Keywords

drug-induced hepatotoxicity
herbal hepatotoxicity
acute and chronic liver damage
pathomechanisms of liver injury
oxidative stress
inflammation
apoptosis and necrosis
fibrosis

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Published Papers (7 papers)

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13 pages, 2356 KiB

Open AccessArticle

Azorella compacta Organic Extracts Exacerbate Metabolic Dysfunction-Associated Fatty Liver Disease in Mice Fed a High-Fat Diet

by Jessica Zúñiga-Hernandez, Matías Quiñones San Martin, Benjamín Figueroa, Ulises Novoa, Francisco A. Monsalve, Mitchell Bacho, Aurelio San-Martin and Daniel R. González

Pharmaceuticals 2024, 17(6), 746; https://doi.org/10.3390/ph17060746 - 6 Jun 2024

Viewed by 995

Abstract

Azorella compacta (A. compacta) is a shrub of the Andean Altiplano of Bolivia, Chile and Peru, consumed by local communities as a traditional medicine for several maladies such as diabetes, hepatic and inflammatory diseases. A. compacta is rich in mulinane- and azorellane-type diterpenoids. For two of these, acute hypoglycemic effects have been described, but the impact of A. compacta diterpenoids on fatty liver disease has not been investigated. Therefore, A. compacta organic fractions were prepared using petroleum ether, dichloromethane and methanol. Their content was characterized by UHPLC/MS, revealing the presence of ten diterpenoids, mainly mulinic acid, azorellanol and mulin-11,13-diene. Next, mice fed with a high-fat diet (HFD), a model of metabolic dysfunction-associated fatty liver disease (MAFLD), received one of the fractions in drinking water for two weeks. After this treatment, hepatic parameters were evaluated. The A. compacta fractions did not reduce hyperglycemia or body weight in the HFD-fed mice but increased the serum levels of hepatic transaminases (AST and ALT), reduced albumin and increased bilirubin, indicating hepatic damage, while histopathological alterations such as steatosis, inflammation and necrosis generated by the HFD were, overall, not ameliorated by the fractions. These results suggest that organic A. compacta extracts may generate hepatic complications in patients with MAFLD. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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15 pages, 4543 KiB

Open AccessArticle

Fasudil Ameliorates Methotrexate-Induced Hepatotoxicity by Modulation of Redox-Sensitive Signals

by Esam M. Aboubakr, Ahmed R. N. Ibrahim, Fares E. M. Ali, Ahmed A. E. Mourad, Adel M. Ahmad and Amal Hofni

Pharmaceuticals 2022, 15(11), 1436; https://doi.org/10.3390/ph15111436 - 19 Nov 2022

Cited by 4 | Viewed by 2076

Abstract

Methotrexate (MTX) is one of the most widely used cytotoxic chemotherapeutic agents, and it is used in the treatment of different autoimmune disorders. However, the clinical applications of MTX are limited by its hepatic toxicity. Hence, the present study was conducted to evaluate the efficacy of fasudil (Rho-Kinase inhibitor) in the amelioration of MTX hepatotoxicity and the possible underlying mechanisms. Experimentally, 32 male Sprague Dawley rats were used and divided into four groups: control, MTX (20 mg/kg, i.p., single dose), fasudil (10 mg/kg/day i.p.) for one week, and fasudil plus MTX. It was found that MTX significantly induced hepatitis and hepatocellular damage, as shown by abnormal histological findings and liver dysfunction (ALT and AST), with up-regulation of the inflammatory mediators NF-κB-p65 and IL-1β. Moreover, MTX remarkably disrupted oxidant/antioxidant status, as evidenced by malondialdehyde (MDA) up-regulation associated with the depletion of superoxide dismutase (SOD), catalase, and reduced glutathione (GSH) levels. Moreover, MTX reduced the hepatic expression of B-cell lymphoma 2 (Bcl-2). On the contrary, the i.p. administration of fasudil significantly ameliorated MTX hepatotoxicity by histopathological improvement, restoring oxidant/antioxidant balance, preventing hepatic inflammation, and improving the hepatic anti-apoptotic capability. Furthermore, fasudil hepatic concentration was determined for the first time using the validated RP-HPLC method. In conclusion, the present study revealed that fasudil has a reliable hepatoprotective effect against MTX hepatotoxicity with underlying antioxidant, anti-inflammatory, and anti-apoptotic mechanisms. It also introduced a new method for the determination of fasudil hepatic tissue concentration using the RP-HPLC technique. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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14 pages, 10403 KiB

Open AccessArticle

Paeonol Protects against Methotrexate Hepatotoxicity by Repressing Oxidative Stress, Inflammation, and Apoptosis—The Role of Drug Efflux Transporters

by Mohamed A. Morsy, Rania Abdel-Latif, Sara Mohamed Naguib Abdel Hafez, Mahmoud Kandeel and Seham A. Abdel-Gaber

Pharmaceuticals 2022, 15(10), 1296; https://doi.org/10.3390/ph15101296 - 21 Oct 2022

Cited by 8 | Viewed by 2409

Abstract

Methotrexate (MTX) is an effective chemotherapeutic agent against a wide range of tumors and autoimmune diseases; however, hepatotoxicity limits its clinical use. Oxidative stress and inflammation have been implicated in the pathogenesis of MTX-induced hepatotoxicity. Paeonol is a natural phenolic compound reported for its antioxidant and anti-inflammatory properties. The current study aimed to investigate the protective effect of paeonol against MTX-induced hepatotoxicity in rats and various mechanisms that underlie this postulated effect. Paeonol was administered orally in a dose of 100 mg/kg, alone or along with MTX, for 10 days. Hepatotoxicity was induced via a single intraperitoneal dose of MTX (20 mg/kg) on day 5 of the experiment. Concomitant administration of paeonol with MTX significantly ameliorated distorted hepatic function and histological structure, restored hepatic oxidative stress parameters (MDA, NO, and SOD), and combated inflammatory response (iNOS and TNF-α). Additionally, paeonol enhanced cell proliferation and survival, evidenced by upregulating the proliferating cell nuclear antigen (PCNA) and suppressing apoptosis and the disposition of collagen fibers in rat livers treated with MTX. Importantly, paeonol upregulated the drug efflux transporters, namely P-glycoprotein (P-gp) and the multidrug resistance-associated protein 2 (Mrp-2) in MTX-treated rats. In conclusion, paeonol offered a potent protective effect against MTX-induced hepatotoxicity through suppressing oxidative stress, inflammation, fibrosis, and apoptosis pathways, along with P-gp and Mrp-2 upregulation. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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17 pages, 8591 KiB

Open AccessArticle

Magnesium Isoglycyrrhizinate Attenuates Anti-Tuberculosis Drug-Induced Liver Injury by Enhancing Intestinal Barrier Function and Inhibiting the LPS/TLRs/NF-κB Signaling Pathway in Mice

by Jin-Yu Gong, Huan Ren, Hui-Qing Chen, Kai Xing, Chen-Lin Xiao and Jian-Quan Luo

Pharmaceuticals 2022, 15(9), 1130; https://doi.org/10.3390/ph15091130 - 9 Sep 2022

Cited by 12 | Viewed by 2756

Abstract

Liver injury caused by first-line anti-tuberculosis (anti-TB) drugs accounts for a high proportion of drug-induced liver injury (DILI), and gut microbiota and intestinal barrier integrity have been shown to be involved in the development of DILI. Magnesium isoglycyrrhizinate (MgIG) is the fourth-generation glycyrrhizic acid preparation, which is well documented to be effective against anti-TB DILI, but the underlying mechanism is largely unclear. In the present study, we established a BALB/c mice animal model of the HRZE regimen (39 mg/kg isoniazid (H), 77 mg/kg rifampicin (R), 195 mg/kg pyrazinamide (Z), and 156 mg/kg ethambutol (E))-induced liver injury to investigate the protective effect of MgIG against anti-TB DILI and underlying mechanisms. The results demonstrated that intraperitoneal injection of MgIG (40 mg/kg) significantly ameliorated HRZE-induced liver injury by reducing alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), and malondialdehyde (MDA) levels and improved liver pathological changes. Species composition analysis of gut microbiota showed that Lactobacillus was the only probiotic that was down-regulated by HRZE and recovered by MgIG. In addition, MgIG attenuated HRZE-induced intestinal pathology, significantly decreased HRZE-induced intestinal permeability by increasing the protein expression of tight junction protein 1 (ZO-1) and occludin, decreased HRZE-induced high lipopolysaccharide (LPS) levels, and further markedly attenuated mRNA expression levels of TNF-α, IL-6, TLR2, TLR4, and NF-κB. Supplementation with Lactobacillus rhamnosus JYLR-005 (>10⁹ CFU/day/mouse) alleviated HRZE-induced liver injury and inflammation in mice. In summary, MgIG effectively ameliorated HRZE-induced liver injury by restoring the abundance of Lactobacillus, enhancing intestinal barrier function, and further inhibiting the activation of the LPS/TLRs/NF-κB signaling pathway. Regulating gut microbiota and promoting the integrity of intestinal barrier function may become a new direction for the prevention and treatment of anti-TB DILI. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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31 pages, 9926 KiB

Open AccessArticle

Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study

by Doaa I. Mohamed, Samar F. Ezzat, Wael M. Elayat, Omnyah A. El-Kharashi, Hanaa F. Abd El-Kareem, Hebatallah H. Abo Nahas, Basel A. Abdel-Wahab, Samar Zuhair Alshawwa, Asmaa Saleh, Yosra A. Helmy, Eman Khairy and Essa M. Saied

Pharmaceuticals 2022, 15(7), 832; https://doi.org/10.3390/ph15070832 - 5 Jul 2022

Cited by 26 | Viewed by 4166

Abstract

Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia–reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (−14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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11 pages, 288 KiB

Open AccessArticle

Liver Injury with Nintedanib: A Pharmacovigilance–Pharmacokinetic Appraisal

by Emanuel Raschi, Michele Fusaroli, Milo Gatti, Paolo Caraceni, Elisabetta Poluzzi and Fabrizio De Ponti

Pharmaceuticals 2022, 15(5), 645; https://doi.org/10.3390/ph15050645 - 23 May 2022

Cited by 10 | Viewed by 3262

Abstract

Drug-induced liver injury (DILI) with nintedanib has emerged as an adverse event of special interest in premarketing clinical trials. We characterized DILI with nintedanib in the real world and explored the underlying pharmacological basis. First, we assessed serious hepatic events reported to the Food and Drug Administration’s Adverse Event Reporting System by combining the disproportionality approach [reporting odds ratio (ROR) with 95% confidence interval (CI)] with individual case assessment. Demographic and clinical features were inspected (seriousness, onset, discontinuation, dechallenge/rechallenge, concomitant drugs) to implement an ad hoc causality assessment scoring system. Second, we appraised physiochemical and pharmacokinetic parameters possibly predictive of DILI occurrence. Significant disproportionality was found for nintedanib as compared to pirfenidone (N = 91; ROR = 4.77; 95% CI = 3.15–7.39). Asian population, low body weight (59 kg), and rapid DILI onset (13.5 days) emerged as clinical features. Hospitalization and discontinuation were found in a significant proportion of cases (32% and 36%, respectively). In 24% of the cases, at least two potentially hepatotoxic drugs (statins, proton pump inhibitors, antibiotics) were recorded. Causality was at least possible in 92.3% of the cases. High lipophilicity and predicted in silico inhibition of liver transporters emerged as potential pharmacokinetic features supporting the biological plausibility. Although causality cannot be demonstrated, clinicians should consider early monitoring and medication review on a case-by-case basis. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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8 pages, 246 KiB

Open AccessCase Report

Herb-Induced Liver Injury by Ayurvedic Ashwagandha as Assessed for Causality by the Updated RUCAM: An Emerging Cause

by Goran Bokan, Tanja Glamočanin, Zoran Mavija, Bojana Vidović, Ana Stojanović, Einar S. Björnsson and Vesna Vučić

Pharmaceuticals 2023, 16(8), 1129; https://doi.org/10.3390/ph16081129 - 10 Aug 2023

Cited by 7 | Viewed by 8145

Abstract

Herb-induced liver injury (HILI) caused by herbal supplements, natural products, and products used in traditional medicine are important for differential diagnoses in patients with acute liver injury without an obvious etiology. The root of Withania somnifera (L.) Dunal, commonly known as ashwagandha, has been used in Ayurvedic medicine for thousands of years to promote health and longevity. Due to various biological activities, ashwagandha and its extracts became widespread as herbal supplements on the global market. Although it is generally considered safe, there are several reported cases of ashwagandha-related liver injury, and one case ended with liver transplantation. In this paper, we review all reported cases so far. Additionally, we describe two new cases of ashwagandha hepatotoxicity. In the first case, a 36-year-old man used ashwagandha capsules (450 mg, three times daily) for 6 months before he developed nausea, pruritus, and dark-colored urine. In the second case, a 30-year-old woman developed pruritus after 45 days of using ashwagandha capsules (450 mg). In both cases, serum bilirubin and liver enzymes (aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP) were increased. The liver injury pattern was hepatocellular (R-value 11.1) and mixed (R-value 2.6), respectively. The updated Roussel Uclaf Causality Assessment Method (RUCAM) (both cases with a score of seven) indicated a “probable” relationship with ashwagandha. Clinical and liver function improvements were observed after the discontinuation of ashwagandha supplement use. By increasing the data related to ashwagandha-induced liver injury, these reports support that consuming ashwagandha supplements is not without its safety concerns. Full article

(This article belongs to the Special Issue Drug-Induced and Herbal Hepatotoxicity and Methods of Its Prevention)

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