By Jessica Lu
Drug-induced liver injury (DILI) is the most common cause of acute liver failure in Europe and in the USA.1 For some drugs such as acetaminophen, DILI is dose-dependent, predictable, and reproducible in preclinical models. However, DILI onset may also be idiosyncratic – characterised by a variable latency to onset (weeks to months) and a lack of clear dose dependency. Idiosyncratic DILI (IDLI) is a major cause of drug candidate failure, responsible for about 10–15% of acute liver failures in the USA. Current understanding of the mechanisms responsible for IDILI is poor, however it is thought to be caused by the intrinsic chemical reactivity of drugs or reactive metabolites. Immune-mediated responses, mitochondrial injury and bile salt export pump (BSEP) inhibition have also been proposed to be involved in IDILI.2
The unpredictable nature of IDILI makes it difficult to avoid, causing problems during drug development.2 Additionally, indication that a drug may cause IDILI (e.g. evidence of liver injury in animals) may severely delay development. Because IDILI is also idiosyncratic in animals, it usually remains undetected through animal toxicology studies.3 In vitro assays also fail to accurately predict IDILI and, oftentimes, its incidence is also rare enough to go undetected during clinical trials, meaning that it is only detected once a drug has been on the market for some time. This can cause the withdrawal of a drug after many resources have already been spent on its development. On the other hand, false-positive DILI adjudication during drug development may lead to the unnecessary attrition of compounds during drug development thus resulting in further waste of resources.1
In addition to causing problems during drug development, the unpredictable nature of IDILI makes it difficult to perform mechanistic studies. Despite this, a variety of possible mechanisms have been proposed. Circumstantial evidence suggests that the cause of most IDILI is related to the intrinsic chemical reactivity of drugs or the reactive metabolites of drugs, but it is difficult to test this hypothesis.2 Generally, however, problematic drugs for IDILI exhibit higher covalent binding to human liver microsomes (HLMs) than safer drugs.4 The fact that these drugs may form more than one reactive metabolite makes it difficult to determine which metabolite is responsible for the IDILI. For example, the drug nevirapine forms btoh a quinone methide that is likely responsible for IDILI and also a reactive sulphate conjugate that is responsible for idiosyncratic skin rash.2
Genetic studies performed on IDILI show that for some drugs, IDILI is may be immune mediated andf may be, for example, associated with specific human leukocyte antigen (HLA) genotypes. For example, the HLA-DRB1*5701 haplotype increases the risk of flucloxacillin-induced IDILI.1,2 However, for most drugs, IDILI is so rare that there are too few cases to determine if an association with HLA genotypes exists, however the fact that IDILI caused by different drugs that share similar characteristics further support the theory that most cases are immune mediated.5 Moreover, though HLA genotype is a risk factor for IDILI, it is not the only risk factor. This is suggested by the fact that serious IDILI is unlikely even when the patient with the specific HLA genotype required is treated with the associated drug.
Another proposed mechanism for IDILI is mitochondrial injury as most drugs that cause DILI have also been shown to cause mitochondrial stress.2,6 When mitochondrial function is inhibited by drugs or reactive metabolites, DILI can occur, however drug-induced mitochondrial stress alone is not sufficient for liver injury to occur as most patients taking idiosyncratic hepatotoxic drugs do not suffer from liver injury. 6 Possibly the reason most patients avoid liver injury is that adaptation pathways such as autophagy/mitophagy, mitochondrial remodelling, and mitochondrial fusion-fission, all involving mitochondria, are upregulated. Furthermore, failure of the liver to adapt may cause IDILI in a small fraction of susceptible patients.6 Once mitochondria become too injured, death signalling pathways involving c-Jun N-terminal kinase (JNK) are activated, resulting in cytochrome c release from mitochondria and hepatocyte death.
Finally, one more proposed mechanism for IDILI is inhibition of the bile salt export pump (BSEP).2,7 Bile acids are toxic and can cause hepatocyte damage and cell stress and several IDILI-causing drugs such as bosentan and nefazodone are BSEP inhibitors. Interestingly, patients with bosentan-induced liver injury have been shown to have higher levels of serum bile acids.5 This proposed mechanism is supported by the fact that complete genetic deficiency of BSEP leads to liver injury and failure5. However, it is unlikely that BSEP inhibition is the sole cause of IDILI due to the exitence of other compensatory mechanisms and bile salt transport proteins such as multidrug resistance protein (MRP) 3 and MRP4. These mechanisms allow for genetic defects causing less severe impairment of BSEP activity to not result in significant liver injury.2 Furthermore, it has been found that measurement of BSEP inhibition in vitro is not a useful predictor of IDILI.8
Overall, IDILI is a major problem for drug development and a common cause of acute liver failure. Many mechanistic hypotheses for IDILI have been proposed, and it is likely that a drug may cause IDILI via a variety of mechanisms. However, much is still uncertain, and more work still needs to be done to understand the issue. In future, better mechanistic understanding would allow better prediction of IDILI, helping to reduce the problems it causes.
References:
(1) Kullak-Ublick GA, Andrade RJ, Merz M, End P, Benesic A, Gerbes AL, et al. Drug-induced liver injury: recent advances in diagnosis and risk assessment. Gut. 2017; 66 (6): 1154-1164. Available from: doi: 10.1136/gutjnl-2016-313369
(2) Uetrecht J. Chapter Five – Mechanisms of idiosyncratic drug-induced liver injury. Advances in pharmacology. 2019; 85 133-163. Available from: doi: 10.1016/bs.apha.2018.12.001
(3) Kenna JG, Uetrecht J. Do In Vitro Assays Predict Drug Candidate Idiosyncratic Drug-Induced Liver Injury Risk? Drug Metabolism and Disposition. 2018; 46 (11): 1658-1669. Available from: doi: 10.1124/dmd.118.082719
(4) Nakayama S, Atsumi R, Takakusa H, Kobayashi Y, Kurihara A, Nagai Y, et al. A Zone Classification System for Risk Assessment of Idiosyncratic Drug Toxicity Using Daily Dose and Covalent Binding. Drug Metabolism and Disposition. 2009; 37 (9): 1970-1977. Available from: doi: 10.1124/dmd.109.027797
(5) Uetrecht J. Mechanistic Studies of Idiosyncratic DILI: Clinical Implications. Frontiers in Pharmacology. 2019; 0 Available from: doi: 10.3389/fphar.2019.00837
(6) Decker CW, Casian JG, Nguyen KT, Horton LA, Rao MP, Silkwood KH, et al. The Critical Role of Mitochondria in Drug-Induced Liver Injury. In: Ding W, Yin X. (eds.) Molecules, Systems and Signaling in Liver Injury. Cham: Springer International Publishing; 2017. pp. 159-181.
(7) Woodhead JL, Yang K, Siler SQ, Watkins PB, Brouwer KLR, Barton HA, et al. Exploring BSEP inhibition-mediated toxicity with a mechanistic model of drug-induced liver injury. Frontiers in Pharmacology. 2014; 5 240. Available from: doi.org/10.3389/fphar.2014.00240
(8) Chan R, Benet LZ. Measures of BSEP Inhibition In Vitro Are Not Useful Predictors of DILI. Toxicological Sciences: An Official Journal of the Society of Toxicology. 2018; 162 (2): 499-508. Available from: doi: 10.1093/toxsci/kfx284
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