Drug-induced liver injury (DILI) is a major problem faced by both healthcare providers as well as patients. Unfortunately, detailed mechanisms of DILI remain largely unknown making its prediction and prevention in the clinic difficult. Many risk factors have been recognized for both "intrinsic" and "idiosyncratic" DILI, indicating the importance of co-factors in understanding DILI. 

The detailed mechanisms of DILI remain obscure for most drugs, but the development of DILI is postulated to occur in 3 steps: (1) exposure of drug and its metabolites to the liver; (2) interactions of drug and its metabolites with molecular targets in the liver, causing cellular dysfunction and injury; and (3) cellular dysfunction and injury trigger cell defence, adaptation, and tissue repair, and improper cell responses causing liver injury. 

Many co-factors potentiating DILI have been identified, which are categorized as the specific and the general co-factors. Specific co-factors augment the DILI risk by directly targeting a specific molecule that is involved in the three steps of liver injury, like an inhibitor of drug-metabolizing enzyme or transporter. 

General co-factors, like inflammation, age, gender, comorbidity, gut microbiota, nutrition, and lifestyle, potentiate DILI by simulating multiple molecules in the process of liver injury. 

The risk factors for DILI can potentially be utilized to predict and prevent DILI, thus improving the safety profile of medications. 

the identification of target molecules of drugs in the liver, mechanistic understanding of DILI and quickening the discovery of novel risk factors for DILI can be facilitated by applying genomics, transcriptomics, proteomics, metabolomics, together with genetically engineered cellular and animal models facilitate. Additionally, the artificial intelligence approaches can also be used for predicting DILI.

SOURCE- Gu R, Liang A, Liao G, To I, Shehu A, Ma X. Roles of co-factors in drug-induced liver injury: drug metabolism and beyond. Drug Metab Dispos. 2022 Feb 27:DMD-MR-2021-000457. doi: 10.1124/dmd.121.000457. Epub ahead of print. PMID: 35221288.