Aluminum, Arsenic, Beryllium, Cadmium, Chromium, Cobalt, Copper, Iron, Lead, Mercury, Molybdenum, Nickel, Platinum, Thallium, Titanium, Vanadium, and Zinc: Molecular Aspects in Experimental Liver Injury

Abstract

Experimental liver injury with hepatocelluar necrosis and abnormal liver tests is caused by exposure to heavy metals (HMs) like aluminum, arsenic, beryllium, cadmium, chromium, cobalt, copper, iron, lead, mercury, molybdenum, nickel, platinum, thallium, titanium, vanadium, and zinc. As pollutants, HMs disturb the ecosystem, and as these substances are toxic, they may affect the health of humans and animals. HMs are not biodegradable and may be deposited preferentially in the liver. The use of animal models can help identify molecular and mechanistic steps leading to the injury. HMs commonly initiate hepatocellular overproduction of ROS (reactive oxygen species) due to oxidative stress, resulting in covalent binding of radicals to macromolecular proteins or lipids existing in membranes of subcellular organelles. Liver injury is facilitated by iron via the Fenton reaction, providing ROS, and is triggered if protective antioxidant systems are exhausted. Ferroptosis syn pyroptosis was recently introduced as mechanistic concept in explanations of nickel (Ni) liver injury. NiCl2 causes increased iron deposition in the liver, upregulation of cyclooxygenase 2 (COX-2) protein and mRNA expression levels, downregulation of glutathione eroxidase 4 (GPX4), ferritin heavy chain 1 (FTH1), nuclear receptor coactivator 4 (NCOA4) protein, and mRNA expression levels. Nickel may cause hepatic injury through mitochondrial damage and ferroptosis, defined as mechanism of iron-dependent cell death, similar to glutamate-induced excitotoxicity but likely distinct from apoptosis, necrosis, and autophagy. Under discussion were additional mechanistic concepts of hepatocellular uptake and biliary excretion of mercury in exposed animals. For instance, the organic anion transporter 3 (Oat3) and the multidrug resistance-associated protein 2 (Mrp2) were involved in the hepatic handling of mercury. Mercury treatment modified the expression of Mrp2 and Oat3 as assessed by immunoblotting, partially explaining its impaired biliary excretion. Concomitantly, a decrease in Oat3 abundance in the hepatocyte plasma membranes was observed that limits the hepatic uptake of mercury ions. Most importantly and shown for the first time in liver injury caused by HMs, titanium changed the diversity of gut microbiota and modified their metabolic functions, leading to increased generation of lipopolysaccharides (LPS). As endotoxins, LPS may trigger and perpetuate the liver injury at the level of gut-liver. In sum, mechanistic and molecular steps of experimental liver injury due to HM administration are complex, with ROS as the key promotional compound. However, additional concepts such as iron used in the Fenton reaction, ferroptosis, modification of transporter systems, and endotoxins derived from diversity of intestinal bacteria at the gut-liver level merit further consideration.

High Levels of Heavy Metal(loid)s Related to Biliary Hyperplasia in Hedgehogs (Erinaceus europaeus)

“…Co (specially CoCl2) has been associated with hepatocellular injuries and -ns [ 16 ], even though the literature is scarce for this element. For human and animal populations, diet (including drinking water) is the main source of Co [ 25 ].…”

“…In general, hepatotoxicity by heavy metal(loids) may be detected elevated levels of liver enzymes (e.g., aspartate aminotransferase, AST; alanine aminotransferase, ALT; or alkaline phosphatase, ALP); elevated levels of necrotic and transforming growth factors; and histopathologic changes. Histopathologic liver changes due to metal(loid) toxicity include (but are not limited to) hydropic alterations, oedema, congestion, inflammatory cell infiltration, necrosis, fibrosis, steatosis and biliary hyperplasia [ 14 , 15 , 16 , 17 ]. Histopathology plays an essential role as a biomarker of the effect of metal(loid)s’ toxicosis, when associated with the detection and measurement of these compounds in biological samples [ 18 , 19 ].…”

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 ].…”

“…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.…”