Idiosyncratic Drug-Induced Liver Injury (IDILI): Potential Mechanisms and Predictive Assays

Table 2

Assays used for determining IDILI potential.

Mechanisms	Proteins	Relevant assays
Phase I DMEs	CYP450	Coumarin metabolism; Fluorescein (CYP2C9); Human liver microsomes (HLMs); High pressure liquid chromatography (HPLC)/Mass spectrometry (MS)
Phase II DMEs	UGT	Coumarin metabolism
	GST (GSTT1 and GSTM1)	CDNB, NBC, DCNB, EPNP, DCM, PBO; GSTT1/GSTM1 single and double knockouts
	UGT/GST/NAT/SULT	Covalent binding level (CBL); HPLC/MS
Antioxidant enzymes	GPx1/SOD2	Monochlorobimane (mBCl); Oxygen consumption rate (OCR); Fluorescein; Tetramethyl rhodamine (TMRM); Cytochrome c release; SOD2^+/- mice
Transporters	BSEP	Vesicular transport assay (VTA); ATPase assay
	MRP2	Fluorescein
	MDR1/MRP2	Flow cytometry
	OCT	OCT1 and OCT2 knockouts
	BSEP/BCRP/MDR/MRP/OATP/OCT/NTCP	HPLC/MS; Drug uptake assays
Inflammation	TNFR1/IFN-γ/TLR9/IL-1/IL-4/IL-6/IL-10/IL-13	LPS-induced inflammation; Lymphocyte transformation test (LTT); Cytokine production; Cytokine knockouts
	CD69	Flow cytometry
HLA	MHC I/MHC II	Flow cytometry

Cytochrome P450 (CYP450), uridine 5′-diphosphate (UDP) glycosyltransferase (UGT), glutathione S-transferase (GST), N-acetyl transferase (NAT), sulfotransferase (SULT), glutathione peroxidase (GPx), superoxide dismutase (SOD), 1-chloro-2,4-dinitrobenzene (CDNB), p-nitrobenzyl chloride (NBC), 1,2-chloro-4-nitrobenzene (DCNB), 2-epoxy-3-(p-nitrophenoxy)propane (EPNP), dichloromethane (DCM), trans-4-phenyl-3-buten-2-one (PBO), lipopolysaccharide (LPS), tumor necrosis factor R1 (TNFR1), interferon gamma (IFN-γ), toll-like receptor (TLR), interleukin (IL), cluster of differentiation (CD), major histocompatibility complex class I (MHC I), and class II (MHC II).