Heavy Metals, Halogenated Hydrocarbons, Phthalates, Glyphosate, Cordycepin, Alcohol, Drugs, and Herbs, Assessed for Liver Injury and Mechanistic Steps

Abstract

Aluminum, arsenic, cadmium, chromium, cobalt, copper, iron, lead, mercury, nickel, thallium, titanium, zinc, carbon tetrachloride, phthalates, glyphosate, alcohol, drugs, and herbs are under discussion having the potential to injure the human liver, but allocation of the injury to the hepatotoxicant as exact cause is difficult for physicians and requires basic clinical knowledge of toxicology details. Liver injury occurs at a variable extent depending on the dose, mostly reproducible in animal models that allow studies on molecular steps leading to the hepatocellular injury. These exogenous hepatotoxins may cause an overproduction of reactive oxidative species (ROS), which are generated during microsomal or mitochondrial oxidative stress from incomplete oxygen split and trigger the injury if protective antioxidant capacities are reduced. Primary subcelluar target organelles involved are liver mitochondria through lipid peroxidation of membrane structures and the action of free radicals such as singlet radical 1 O2, superoxide radical HO•2, hydrogen peroxide H2O2, hydroxyl radical HO•, alkoxyl radical RO•, and peroxyl radical ROO•. They attempt covalent binding to macromolecular structural proteins. As opposed to inorganic chemicals, liver injury due to chemicals with an organic structure proceedes via the hepatic microsomal cytochrome P450 with its different isoforms. In sum, many exogenous chemicals may have the potential of liver injury triggerd by overproduced ROS leading primarily to impairment of mitochondial functions in the course of structural mitochondial membrane dearrangement. As clinical data were often incomplete, future clinical prototols should focus on meeting liver injury criteria, exclusion of alternative causes, a robust causality evaluation management, and obtaining liver histology if clinically indicated and of benefit for the patient.

Single-cell transcriptome analysis reveals liver injury induced by glyphosate in mice

“…S1A). The reported pathological features of the liver after GLY exposure were cytoplasmic vacuolation, degeneration of hepatocytes, steatosis, multifocal necrosis, leukocyte infiltration, massive deposition of reticular fibers, and cytoplasmic glycogen deposition in hepatocytes [16,[34][35][36]. The histopathological effects of GLY on liver tissue in our study are in accordance with these studies using laboratory rats.…”

Molecular Idiosyncratic Toxicology of Drugs in the Human Liver Compared with Animals: Basic Considerations

“…By convention, DILI is caused by regulatory approved drugs, which may have the potential of causing idiosyncratic or intrinsic liver injury [ 2 , 3 , 6 , 27 , 34 ]. Idiosyncratic liver injury is due to the interaction between the drug used in recommended daily doses and a susceptible individual [ 6 , 27 ], whereby this type of injury can be caused by virtually any conventional drug [ 7 ]. As opposed, intrinsic liver injury occurs through drug overdose like paracetamol syn acetaminophen or syn N-acetyl-p-aminophenol (APAP) as the best-known clinical example [ 6 ].…”

“…Idiosyncratic liver injury is due to the interaction between the drug used in recommended daily doses and a susceptible individual [ 6 , 27 ], whereby this type of injury can be caused by virtually any conventional drug [ 7 ]. As opposed, intrinsic liver injury occurs through drug overdose like paracetamol syn acetaminophen or syn N-acetyl-p-aminophenol (APAP) as the best-known clinical example [ 6 ]. Consequently, patients with idiosyncratic DILI used their drugs commonly for some days, weeks, or months, while in the context of an acute intoxication the drug intake is mostly limited to one or two days exceeding the daily allowance of daily dose but can also develop after high cumulative drug doses taken over a longer period [ 6 , 7 ].…”

“…As opposed, intrinsic liver injury occurs through drug overdose like paracetamol syn acetaminophen or syn N-acetyl-p-aminophenol (APAP) as the best-known clinical example [ 6 ]. Consequently, patients with idiosyncratic DILI used their drugs commonly for some days, weeks, or months, while in the context of an acute intoxication the drug intake is mostly limited to one or two days exceeding the daily allowance of daily dose but can also develop after high cumulative drug doses taken over a longer period [ 6 , 7 ]. To facilitate an overview of drugs most implicated in DILI with verified diagnosis as assessed for causality using RUCAM, a list of selected drugs is provided in alphabetical order ( Table 1 ) [ 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 ], with additional details published earlier [ 53 , 54 ].…”

“…The potential risk of liver injury by the use of conventional drugs [ 1 , 2 , 3 ] is shared by a variety of other toxicants such as phytochemicals found in regulatory approved herbal drugs or non-approved herbal medicines like Traditional Chinese Medicines (TCM) [ 4 , 5 ]. Humans may also experience liver injury due to aluminum, arsenic, beryllium, cadmium, chromium, cobalt, copper, iron, lead, mercury, molybdenum, nickel, platinum, thallium, titanium, vanadium, zinc, carbon tetrachloride and herbicides [ 6 , 7 ] as well as pesticides [ 8 ] amanitin of Amanita phalloides [ 9 ], aflatoxins [ 10 ], plants containing 1,2-unsaturated pyrrolizidine alkaloids (PAs), contaminating food or drinking water [ 11 , 12 ], and alcoholic beverages [ 13 , 14 , 15 , 16 , 17 , 18 ]. The diagnosis of liver injury due to most of these compounds can be achieved by exposure history, clinical features, diagnostic biomarkers, and after careful exclusion of alternative causes.…”