Current Drug Safety, 2007, 2, 000-000 1 1574-8863/07 $50.00+.00 © 2007 Bentham Science Publishers Ltd. Genetic and Molecular Factors in Drug-Induced Liver Injury: A Review Ketevan Pachkoria *,1 , Mª Isabel Lucena 1 , Mariam Molokhia 2 , Raquel Cueto 1 , Alfonso Serrano Carballo 3 , Alfonso Carvajal 4 and Raúl J. Andrade 4 1 Clinical Pharmacology Service and 4 Liver Unit, University Hospital Virgen de la Victoria, School of Medicine. Málaga, Spain; 2 Department of Epidemiology & Population Health London School of Hygiene & Tropical Medicine, 3 Servicio de Inmunologia, Hospital Virgen de la Victoria, Málaga, Spain; 4 Instituto de Farmacoepidemiologia de la Universidad de Valladolid, Spain Abstract: The diagnosis of drug-induced liver injury (DILI) is challenging and based on complex diagnostic criteria. DILI falls into two main categories i) intrinsic “dose-dependent” Type A reactions ii) "idiosyncratic” or Type B reactions (which are usually not predictable). Idiosyncratic reactions can be immunoallergic (hypersensitivity), or metabolic, al- though overlap between categories can occur. The aim of this review is to summarise the general view of underlying mechanisms in DILI and to highlight individual risk factors for developing hepatotoxicity. Polymorphisms of bioactiva- tion/toxification pathways through CYP450 enzymes (Phase I), detoxification reactions (Phase II) and excretion/transport (Phase III) are explored together with immunological factors in hepatotoxicity. The importance of establishing a multidis- ciplinary and multicentric network to promote the understanding and research in hepatotoxicity is underlined. Challenges such as genetic analyses for association studies and whole genome studies, pharmacogenetic testing and future approaches to study DILI are considered. Knowledge regarding these operational mechanisms could provide further insight for the prospective identification of susceptible patients at risk of developing drug-induced hepatotoxicity. Keywords: Drug-induced liver injury (DILI), molecular mechanism of DILI, genetic polymorphism, Phase I, II and III en- zymes, genetic testing. 1. GENERAL OVERVIEW OF DILI DILI is a challenge in modern pharmacology and remains the single leading cause of drug withdrawal despite of a rig- orous preclinical and clinical review process [1-3]. DILI has been linked to nearly one thousand drugs used in clinical practice [4] and it also nowadays accounts for more than 50% of the cases of acute liver failure in the USA [2]. The main drug classes associated with DILI are: anti- bacterial agents, nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics [5, 6], perhaps because they repre- sent the most commonly prescribed drugs. Although data to accurately estimate occurrence of DILI are lacking, the fre- quency of unpredictable hepatotoxicity associated with the use of medication is suggested to be around 1 per 10, 000 to 1 per 100,000 exposed individuals [7, 8]. In addition, the incidence of DILI remains largely under- estimated in general population because of under-reporting, difficulties in diagnosis, variation of the clinical setting and incomplete examination of exposed individuals. In a French general population, the frequency of DILI was estimated to be about 14 per 100.000 inhabitants per year [9]. Besides this, a recent study suggests that 1% of medical inpatients develop DILI during the course of hospitalization [10]. One of the major challenges on DILI is to understand the envi- ronmental and genetic factors that are operating and to iden- tify individual susceptibility to idiosyncratic liver injury. The *Address correspondence to this author at the Unidad de Hepatología, De- partamento de Medicina, Facultad de Medicina, Boulevard Louis Pasteur, 32, 29071-Málaga, Spain; Tel: +34 952 134242; Fax: +34 952 131511; E- mail: andrade@uma.es present review examines current concepts of molecular mechanism related to the pathogenesis of hepatotoxicity. 2. GENETIC MECHANISMS OF DILI The general view on the pathogenesis of DILI is that par- ent compounds are rendered hepatotoxic during cytochrome (CYP) 450 metabolism and can exert their action within the target cell [11], although other metabolic pathways can con- tribute. However, data on CYP polymorphism in DILI are lacking apart from anecdotal reports. Below we will discuss the impact of Phase I, II and III enzymes polymorphism and susceptibility to develop DILI. Phase I, II, III Reactions Drug metabolism encompasses three Phases: Phase I, or bioactivation/toxification reactions though CYP450 en- zymes, Phase II, or detoxification reactions (synthetic conju- gations with glucuronic acid, sulfate, glutathione, acetate, and amino acids) and Phase III (excretion/transport). During toxification (Phase I) reactions, introduction of functional group (-OH, -NH2, -SH or –COOH) take place thus making the chemical compound more water soluble. Indeed, water- solubility of chemical compound further continues in detoxi- fication (Phase II). Ultimately, hydrophilic drug metabolites may be exported by Phase III proteins located at the hepato- cyte or cholangiocyte apical canalicular membrane (MRP family, MDR) that shift chemical compounds into the sinu- soidal circulation or bile. Slight imbalance of Phase I, II and III Phases might have important chemical consequences, leading to covalent binding, lipid peroxidation, oxidative stress or glutathione depletion. Polymorphic microsomal enzymes appear to play a role in hepatotoxicity with various compounds.