Quick Definition
What is DILI (Drug-Induced Liver Injury)?: Drug-induced liver injury (DILI) is hepatotoxicity caused by a pharmaceutical drug or herbal supplement. It is the most common cause of acute liver failure in Western countries and the leading cause of drug withdrawal from the market post-approval. DILI ranges from asymptomatic liver enzyme elevation to fulminant hepatic failure.
How does BSEP inhibition cause DILI?
BSEP (ABCB11) is the primary transporter responsible for secreting bile salts from hepatocytes into bile. Drugs that inhibit BSEP cause bile salt accumulation inside hepatocytes. At toxic concentrations, bile salts disrupt mitochondrial membrane potential, generate reactive oxygen species, activate the intrinsic apoptosis pathway, and cause direct membrane lysis. The clinical result is cholestatic hepatitis — a pattern characterised by disproportionate alkaline phosphatase and GGT elevation relative to transaminases.
Examples of BSEP inhibition-mediated DILI
Troglitazone (withdrawn 2000), bosentan (black box warning), cyclosporin A (clinical monitoring required), and rifampicin all cause cholestatic DILI through BSEP inhibition. In vitro BSEP IC50 values for these drugs correlate with their clinical hepatotoxicity risk — validating the vesicular transport assay as a predictive preclinical tool.
How is DILI risk assessed preclinically?
BSEP inhibition is assessed using the inside-out membrane vesicle assay with taurocholic acid as probe substrate. The IC50 is compared to estimated unbound hepatic drug concentration. Additional DILI risk signals come from: MRP2 inhibition, mitochondrial membrane potential disruption (JC-1 assay), reactive metabolite formation (GSH trapping), and covalent protein binding.
Key Facts
- DILI accounts for approximately 50% of acute liver failure cases in the US and is the leading reason for post-marketing drug withdrawal
- Two main mechanisms: direct (intrinsic, dose-dependent, predictable) and idiosyncratic (immune-mediated, unpredictable, rare but severe)
- BSEP (bile salt export pump) inhibition is the primary mechanism of cholestatic DILI — caused by intracellular bile salt accumulation in hepatocytes
- Key DILI biomarkers: ALT, AST (hepatocellular), alkaline phosphatase, GGT (cholestatic), bilirubin (severity marker)
- Hy's Law: ALT >3× ULN + bilirubin >2× ULN without cholestasis = high risk of fatal DILI (~10% mortality)
- In vitro DILI prediction: BSEP inhibition assay, MRP2 inhibition assay, mitochondrial toxicity assay, reactive metabolite (GSH trapping) assay
- ICH M12, EMA and PMDA recommend BSEP inhibition testing as part of IND-enabling DMPK safety package
Further Reading
BSEP Vesicle Kit for DILI Risk Assessment — SeamlessBio
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