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Drug-Induced Liver Injury
Idiosyncratic drug-induced liver injury (DILI) is a type of hepatic injury caused by an uncommon drug adverse reaction that can develop to conditions spanning from asymptomatic liver laboratory abnormalities to acute liver failure (ALF) and death.
Drug-induced liver injury (DILI) is an adverse reaction caused by exposure to drugs and herbal medicines or other xenobiotics. Depending on the presumed mechanism of action of the causative drug, DILI is typically classified as intrinsic (direct) or idiosyncratic , although indirect injury is emerging as a third type . Intrinsic DILI is related to the cytotoxic properties of the causative drug or its metabolite(s). In this case, liver injury is dose-dependent and predictable, and damage can be reproduced in animal models . Acetaminophen (APAP) toxicity is the most common cause for this type of DILI . In contrast, idiosyncratic DILI is mostly host-dependent, multifactorial and unpredictable, since it is determined by both the properties of the drug and its interaction with environmental and host factors . Idiosyncratic DILI is usually not dose-dependent, although the exposure to a threshold dose in each susceptible individual is necessary . Moreover, the delay between starting the drug and the onset of clinical signs of liver injury is another characteristic of idiosyncratic DILI. Indirect liver injury is caused by an indirect action of the drug on liver or immune system, and can induce a new liver condition or exacerbate a preexisting one, such as worsening of hepatitis B or C.
The lines that distinguish types of hepatotoxicity are blurred, and majority of drug-induced liver reactions are considered idiosyncratic. Indeed, this is an unresolved issue and rather an academic classification as research over the last years has demonstrated that there are host susceptibility factors that influence the risk of intrinsic damage and, on the contrary, for drugs that are believed to cause idiosyncratic liver damage, there might be a dose threshold. Therefore, unless stated otherwise, the term DILI is used for idiosyncratic drug-induced hepatotoxicity in this review.
2. Potential Mechanisms Involved in DILI Pathogenesis
The liver plays an important role in metabolizing drugs or exogenous toxicants, protecting the organism from potential toxic chemicals . Bioactivation processes of parent drugs rendering reactive metabolites and the mechanisms involved in detoxification and excretion of xenobiotics (most of them under genetic control) are critical for understanding the mechanisms of DILI . However, many different hypotheses have been proposed due to the multivariant nature of the disease .
2.1. Drug Factors
2.2. Metabolic Mechanisms
2.3. BSEP Inhibition
2.4. Activation of the Immune Response
It has been increasingly clear that the immune response during DILI is determinant, since the presence of T cells and immune system activation in patients with DILI have been observed . The immune response consists of a hypersensitivity reaction which provokes an inflammatory response that involves the innate and the adaptive immune system. Different hypotheses have been suggested to explain drug-induced immune system activation .
2.4.1. The Hapten Hypothesis
2.4.2. The Danger Hypothesis
2.4.3. The Pharmacological Interaction (p-i) Hypothesis
2.4.4. The Altered Peptide Repertoire Hypothesis
2.4.5. The Multiple Determinant Hypothesis
2.4.6. The Inflammatory Stress Hypothesis
This hypothesis suggests that a potential inflammation occurring during drug treatment could interact with the action of the compound and produce liver injury . Hepatic inflammation is often observed in DILI; therefore, it is suggested that DILI reactions could be unmasked by inflammation occurring during drug therapy. Inflammagens could bind to TLR or T-cell receptors (TCR), initiating the expression of inflammatory mediators. The inflammatory stress hypothesis has provided the first animal models in which liver injury is induced from different drugs associated with human DILI .
Moreover, a common mechanism of immune response involves activation of the inflammasome . A recent study showed that the supernatant (presumably containing DAMPs) from the incubation of human hepatocytes with drugs that induce DILI activates the inflammasome in THP-1 cells, a macrophage cell line .
The entry is from 10.3390/antiox10030390
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