ABSTRACT
I. Introduction II. Adduct Formation as a Pathogenic Mechanism in Immune-Mediated Drug-Induced
Hepatitis III. Hepatitis in APS-1: A Single Gene Defect Causes Immune-Mediated Hepatitis and
Other Autoimmune Diseases IV. Autoimmune Hepatitis Type 2 V. Conclusions
Acknowledgment References
I. INTRODUCTION Liver injury by drugs may be caused by direct toxicity of a drug, which is dependent on the structure and the metabolic properties of the drug itself and leads to damage of cellular compounds such as proteins, lipids, or DNA. Direct toxicity of a drug occurs in the majority of patients and may be reproducible in animal models. In a small percentage of patients, however, severe adverse drug reactions are noted that are either mediated by the immune system or due to metabolic idiosyncrasies direct toxicity in rare susceptible individuals. We will focus on immunopathogenetic reactions. These adverse reactions often affect the liver and are mediated by activation of the drug to reactive metabolites that modify liver proteins, mostly the cytochrome P450 (CYP) that generate them. An immune reaction
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directed against modified and native CYPs results in an immune-mediated attack on hepatocytes that causes severe, sometimes life-threatening hepatitis. Mechanisms involved in drug-induced hepatitis will be discussed with tienilic acid-induced hepatitis, dihydralazine hepatitis, halothane hepatitis, anticonvulsant hepatitis, and diclofenac hepatitis as examples. Since the prevalence of drug-induced hepatitis is 1:10,000 or less, adduct formation alone will not result in drug-induced hepatitis. Defects and polymorphisms in immunoregulatory genes that facilitate autoimmune reactions have to be postulated.
