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Dean, College of Agriculture, California State Polytechnic University, Pomona, Pomona, California
Drug Induced Liver Disease. Neil Kaplowitz and Laurie D. DeLeve, eds. New York: Marcel Dekker, 755 pp, 2003.
During the last 20 years, this topic has attracted more and more interest. The need for accurate information and a better understanding of mechanisms related to liver disease has been increased by greater use of over-the-counter (OTC) drugs and greater prescription of multiple pharmaceutics for treatment of our ailments.
The volume is exceptionally well written, using an international array of authors. Each author is well recognized in the specialty areas each has reviewed for the book, including pathogenesis, clinical pathology, toxicology, immunology, pharmacology and molecular biochemistry. The quality of the authors’ efforts makes the book stimulating to read. Those readers with knowledge in a few areas will be able to broaden their perspectives, while those with limited knowledge will be able to develop new areas of interest. Young faculty and graduate students especially will find this volume useful, as will research scientists.
The book is presented in four sections emphasizing Mechanisms, Diagnosis and Management, Hepatotoxicity of Specific Drugs and Regulatory Perspectives.
The first chapter presents an overview of drug-induced liver disorders. Eleven types of hepatic liver diseases are introduced, described and discussed. Emphasis in this section is on characterization of specific mechanisms and the resultant cellular damage leading to toxicity. Another chapter discusses the role of the hepatic drug metabolizing enzymes in the process, particularly, the role of cytochrome P450 in drug induced toxicity. Specific drugs were identified as molecular probes to study the cytochrome P450 enzymes in man and animal. Individual cytochrome P450s are induced by specific drugs, and other drugs act as specific inhibitors of cytochrome P450 metabolism. Individual P450 isoenzymes can then be isolated, reconstituted into active complexes and studied further by utilizing recombinant P450 isoenzymes to metabolize specific drugs. The use of molecular biology has proven very useful in these studies.
Many sites of damage may be targeted. An exceptional review of reactive oxygen species, oxidant sources and resultant damage is presented, leading to characterization of the role of cellular antioxidant mechanisms, both enzymatic and chemical. Apoptosis is discussed in relation to drug-induced cell death. A remarkable discussion on apoptosis and the intricate cascade leading to cell death is presented. Intracellular stress pathways are described emphasizing the central role of mitochondria. Details of the individual mechanisms in these pathways are less than clear, but the overall process is described. This process is distinct from necrotic cell death, which results in lysis following loss of active transport and the ability to maintain gradients. The distinction between apoptosis and necrosis in hepatotoxicity is less well studied. Most work has focused on direct acting hepatotoxins, while the idiosyncratic delayed reactions remain unknown.
A concise yet thorough discussion of mitochondrial damage as a target for drug-induced toxicity is impressive. Impaired metabolism and respiration, electron flow, oxygen radicals, altered mDNA, inhibition of B-oxidation all contribute to disruption of mitochondrial function. Another area of membrane damage is described for the bile transporters. While drug transporters have been identified, the details of specificity are in early development. P-glycoproteins and multi-drug resistance-associated proteins (first identified in cancer chemotherapy) provide the key areas of interest currently.
Three types of immune-related hepatotoxicity mechanisms can be identified: drug-induced hepatitis, hepatitis in APS-1 and autoimmune hepatitis type 2. All are characterized by circulating antibodies that target drug metabolizing enzymes (anti-CYP and anti-UGT1A). However, much more work is needed to clarify the differences in mechanism.
Chemically induced toxicity is a multifactorial process involving direct tissue injury as well as a cascade of protein and lipid mediators generated by cells within the liver. Active participants include hepatocytes, Kupffer cells, stellate cells and endothelial cells, but also infiltrating leukocytes. These cells generate a variety of mediators, including cytokines, nitric oxide, peroxynitrite, superoxide anion, hydrogen peroxide, hydroxyl radicals and eicosinoids that may be cytotoxic and proinflammatory and can compromise normal liver function. To prevent damage, precise characterization of each in tissue injury is essential.
In the section on diagnosis and management, two chapters focus on the clinical presentation of the pathology patterns and the management of drug-induced liver injury. The chapter includes the spectrum of drug-induced liver disorders; the types of injury, specific features and selected examples were presented. The second chapter focuses more on the histopathology of drug-induced liver disease, indicating the changes are complex. Drug- and toxin-induced liver cell injury is characterized by eliminating other causes of disease, including discontinuing the therapy and monitoring hepatic function. The chapter separates the drugs and toxins into the key histological features seen on biopsy, such as morphological variants, lob necrosis with or without inflammation, confluent necrosis with inflammation fatty change and granulomas. Strategies are presented to monitor patients at risk and identify preventive measures to be used.
The third section provides a systematic review of specific toxins implicated in drug-induced hepatotoxicity. A critical discussion is presented of unique problems related to specific agents, such as acetaminophen, non-steroidal anti-inflammatory, anesthetic agents, anticonvulsants, psychotropic, drug abuse, anti-bacterial and antifungal, antiviral, cardiovascular, antidiabetic, cancer chemotherapy, immuno-modulators, hormones and hormone analogs. Natural agents used in alternative medicine and occupational and environmental hepatotoxicity round out the section. The concluding chapter provides a brief but thorough overview of regulatory processes and needs.
The text presents a thorough overview of the entire field of drug-induced liver disease. The editors are to be complimented for their successful effort to keep the presentations consistent and sharp. The figures and tables are useful and complemented the text. The references are thorough and up-to-date as well. The discussions provide insight into prediction, prevention and treatment of drug induced liver disease. Researchers, educators, graduate students and clinical specialists will enjoy the volume and find it useful as a desk reference.
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