Ch3conhnhcoch3

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/'' Toxic Metabolite

Hepatocellular Necrosis

FIGURE 16.6 Metabolism of isoniazid to hydrazine, which is then activated by cytochrome P450 enzymes to a chemically reactive metabolite. N-Acetyltransferase (NAT2) acts at several points in this scheme to reduce hydrazine concentrations. This accounts for the fact that rapid acetylators are less likely than slow acetylators to develop isoniazid-induced hepatitis. On the other hand, chronic alcohol consumption induces cytochrome P450 enzymes, thereby increasing the extent of toxic metabolite formation from hydrazine and the risk of hepatitis.

/'' Toxic Metabolite

FIGURE 16.6 Metabolism of isoniazid to hydrazine, which is then activated by cytochrome P450 enzymes to a chemically reactive metabolite. N-Acetyltransferase (NAT2) acts at several points in this scheme to reduce hydrazine concentrations. This accounts for the fact that rapid acetylators are less likely than slow acetylators to develop isoniazid-induced hepatitis. On the other hand, chronic alcohol consumption induces cytochrome P450 enzymes, thereby increasing the extent of toxic metabolite formation from hydrazine and the risk of hepatitis.

needed for a molecule to elicit an immune response, most drugs elicit immune responses by functioning as haptens. In most cases this entails initial formation of a chemically reactive metabolite that then binds covalently to a macromolecule to form a neoantigen. The reactive metabolite may in some cases function as a direct hepatotoxin as well as an immunogen (37) (see Figure 16.4). The enzyme that metabolizes the drug may be among the macromolecular targets and may subsequently be inactivated by the reactive metabolite, a phenomenon referred to as suicide inhibition. After transport of the neoantigen to the cell membrane, humoral or cellular immune responses are triggered and result in hepatocellular damage.

Traditionally, immune mediated toxicity has been suspected on clinical grounds, such as the presence of fever, rash, an eosinophil response, a delay between exposure to the toxin and the onset of clinical symptoms, and the accelerated recurrence of symptoms and signs of toxicity after readministration of the drug (38). However, recent investigations have began to provide a framework for understanding the mechanism of these reactions.

Halothane

Halothane is a volatile general anesthetic that was introduced into the practice of clinical anesthesia in 1956. Shortly after its introduction, two forms of hepatic injury were noted to occur in patients who received halothane anesthesia. A subclinical increase in blood concentration of transaminase enzymes is observed in 20% of patients and has been attributed to lipid peroxidation caused by the free radical formed by reductive metabolism of halothane, as shown in Figure 16.7 (39, 40). The second form of toxicity is a potentially fatal hepatitis-like reaction that is characterized by severe hepatocellular necrosis and is thought to be initiated by the oxidative formation of trifluoroacetyl chloride (Figure 16.7). Fatal hepatic necrosis occurs in only 1 of 35,000 patients exposed to halothane, but the risk of this adverse event is greater in females and is increased with repeat exposure, obesity, and advancing age (40). Because the onset of halothane hepatitis is delayed but is more frequent and occurs more rapidly following multiple exposures, and because these patients usually are febrile and demonstrate eosinophilia, this reaction is suspected of having an immunologic basis. This hypothesis is strengthened by the finding that serum from patients with halothane hepatitis contains antibodies that react specifically with the cell membrane of hepatocytes harvested from halothane-anesthetized rabbits, rendering them susceptible to the cytotoxic effects of normal lymphocytes (38).

Satoh et al. (41) have further elucidated the mechanism of halothane hepatitis by demonstrating that the reactive acyl chloride metabolite shown in Figure 16.7 binds covalently to the surface membranes of hep-atocytes of rats injected with halothane. Among the macromolecular targets of this metabolite is CYP2E1. This is the cytochrome P450 isoform that predominates in forming trifluoroacetyl chloride from halothane, and 45% of patients with halothane hepatitis form autoantibodies against CYP2E1 as well as antibodies against neoantigens formed by this reaction (42). A number of other macromolecular targets are located in the endoplasmic reticulum, where they appear to act as chaperones involved in protein folding (43). At present, it is not certain that these antibodies play a pathogenetic role in halothane hepatitis, and it is possible that cell-mediated immune mechanisms might be of greater importance. In that regard, Furst et al. (44) have demonstrated that Kupffer cells are involved as antigen-presenting cells in a guinea pig model of halothane hepatitis.

CYP3A4, 2A6 Reduction

CF3 I Br H

Halothane

CYP2E1, 2A6 Oxidation

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