Toxicity liver, drug-induced

Klatskin G, Toxic and Drug Induced Hepatitis. In Diseases of the liver, 4th Ed, L Schiff (ed),... 

Of course, Rezulin is nof fhe only drug implicated in liver toxicity. In fact, the FDA recently posted a nottce on its website (http //fda.gov/), describing a special interesf and monitoring of drug-induced hepatotoxicity ... 

In contrast to these concentrations many clinically-used drugs, which are non-inducers are effective at doses up to two orders of magnitude lower. The need for high doses has other undesirable complications. As outlined above dose size is important in toxicity and enzyme inducers show a high level of adverse drug reactions affecting such organs and tissues as the liver, blood and skin (Table 8.4). 

Liver injury is clinically defined as an increase of serum alanine amino transferase (ALT) levels of more than three times the upper limit of normal and a total bilirubin level of more than twice the upper limit of normal [4]. The clinical patterns of liver injury can be characterized as hepatocellular (with a predominant initial elevation of ALT), cholestatic (with an initial elevation of alkaline phosphatase) or mixed. The mechanisms of drug-induced hepatotoxicity include excessive generation of reactive metabolites, mitochondrial dysfunction, oxidative stress and inhibition of bile salt efflux protein [5]. Better understandings of these mechanisms in the past decades led to the development of assays and models suitable for studying such toxic mechanisms and for selecting better leads in the drug discovery stage. 

Drug-induced hepatotoxicity can present in variable manifestations, such as cell death (necrosis, apoptosis), infiammation, degeneration (steatosis), fibrosis/cirrho-sis and the development of tumors. The manifestations of drug toxicity may not be mutually exclusive and may occur sequentially, or in combination. ALT and ALP can be used to generally classify the pattern of liver injury as either hepatocellular (ALT >3x ULN), cholestatic (ALP >2x ULN, ALT/ALP <2) or mixed (elevated ALP and ALT). The successful monitoring of hepatotoxicity would identify cases before irreversible injury occurs. The activity levels of ALT, AST and ALP only increase after hepatic or cholestatic injury has occurred. Waiting for activity levels to exceed the established thresholds may be too late [3]. New biomarkers are needed to monitor/predict the specific sequence of events for different classes of hepatotoxic compounds. 

Chemical injuries to the liver depend on the type of toxic agent, the severity of intoxication, and the type of exposure, whether acute or chronic. The six basic types of liver damage are fatty liver, necrois, hepatobiliary dysfuntions, viral-hke hepatitis, and (on chronic exposure) cirrhosis and neoplasia. A number of organic chemicals and drugs induce fatty liver and hver necrosis. 

Toxicities are numerous and include nephrotoxicity, hypertension, hyperglycemia, liver dysfunction, hyperkalemia, altered mental status, seizures, and hirsutism. Cyclosporine causes very little bone marrow toxicity. While an increased incidence of lymphoma and other cancers (Kaposi s sarcoma, skin cancer) have been observed in transplant recipients receiving cyclosporine, other immunosuppressive agents may also predispose recipients to cancer. Some evidence suggests that tumors may arise after cyclosporine treatment because the drug induces TGF-B, which promotes tumor invasion and metastasis. 

Although the CYP enzymes are the most abundant in the liver, they are also present in other tissues including the skin, kidney, intestine, lung, placenta, and nasal mucosa. Because CYP exists as multiple isozymes with different substrate specificities, the presence or absence of a particular CYP isozyme may contribute to tissue-specific toxicities. Many drugs and other foreign compounds are known to induce one or more of the CYP isozymes, resulting in an increase, decrease, or an alteration in the metabolic pathway of chemicals metabolized by the CYP isozymes involved. Specific examples of these types of interactions are given later in this section. 

Liver drug toxicity may be increased by enzyme inducers and a number of examples are known. Thus, carbon tetrachloride (16), trichlor-ethylene (17), toluene (18), hycanthone (19), acetaminophen and isoniazid (20), and metotrexate (21), among other drugs and chemicals, have been studied in this respect. 

TABLE 16.2 Classification of Drug-Induced Liver Toxicity... 

Fig. 29.1 Diagram illustrating potential pathogenetic mechanisms related to drug-induced toxic liver damage...

Three forms of drug-induced liver failure are distinguished (1.) obligate, dose-dependent toxicity (e. g. paracetamol, (s. fig. 20.3), (2.) unpredictable, idiosyncratic liver insufficiency (e.g. isoniazid), and (3.) immunoaller-gic idiosyncrasy (e.g. halothane) (s. fig. 29.2). 

Liver damage caused by drug-induced toxicity, more specifically the intrahepatic obstructive type of jaundice resulting from the intake of arsphenamine, was first described by EM. Hanger et al. in 1940. (42)... 

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