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Drug-Induced Liver Injury

  • Michael Holt
  • Cynthia JuEmail author
Chapter
Part of the Handbook of Experimental Pharmacology book series (HEP, volume 196)

Abstract

Many drugs and environmental chemicals are capable of evoking some degree of liver injury. The liver represents a primary target for adverse drug reactions due to its central role in biotransformation and excretion of foreign compounds, its portal location within the circulation exposing it to a wide variety of substances, and its anatomic and physiologic structure. Drug-induced liver injury (DILI) remains the single most common adverse indication leading to drug candidate failure or withdrawal from the market. However, the absolute incidence of DILI is low, and this presents a challenge to mechanistic studies. DILI remains unpredictable making prevention very difficult. In this chapter, we focus on the current understanding of DILI. We begin with an overview regarding the significance and epidemiology of DILI and then examine the clinical presentation and susceptibility factors related to DILI. This is followed by a review of the current literature regarding the proposed pathogenesis of DILI, which involves the participation of a drug, or most often a reactive metabolite of the drug, that either directly affects cellular function or elicits an immune response. It is our hope that this chapter will shed light on the major problems associated with DILI in regards to the pharmaceutical industry, drug regulatory agencies, physicians and pharmacists, and patients.

Keywords

Liver Drug Metabolite Adduct Immune response 

Abbreviations

DILI

Drug-induced liver injury

US

United States

FDA

Food and Drug Administration

APAP

Acetaminophen

NSAIDs

Nonsteroidal antiinflammatory drugs

PPAR

Peroxisome proliferator activated receptor

ALT

Alanine aminotransferase

ULN

Upper limit of normal

AP

Alkaline phosphatase

HIV

Human immunodeficiency virus

HLA

Human leukocyte antigen

CYP450

Cytochrome P450

p-i

concept Direct pharmacological interaction of drugs with immune receptors

APC

Antigen presenting cell

SMX

Sulfamethoxazole

SMX-NHOH

Hydroxylamine metabolite of SMX

SMX-NO

Nitroso-SMX

NK

Natural killer

NKT

NK cell with T cell receptor

DAMP

Damage-associated molecular pattern

TNF

Tumor necrosis factor

IL

Interleukin

IFN

Interferon

COX

Cyclooxygenase

TFA

Trifluoroacetic acid

iNOS

Inducible nitric oxide synthase

LPS

Lipopolysaccharide

polyI:C

Polyinosinic-polycytidylic-acid

TLR

Toll-like receptor

NKG2D

A lectin-like stimulatory receptor originally identified on NK cells

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© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity of Colorado DenverAuroraUSA

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