Reactive intermediate-mediated damage

ROS, or repair the macromolecular damage (Fig. 4). If there is an imbalance favoring accumulation of the reactive intermediate and/or macromolecular damage, that individual can experience developmental toxicity at a therapeutic dose or concentration of a drug, or a normally safe level of exposure to an environmental chemical. Particularly for reactive intermediate-mediated mechanisms, most of the data are derived from animal studies, and very little has been confirmed in humans. 

In general, biotransformation reactions are beneficial in that they facilitate the elimination of xenobiotics from pulmonary tissues. Sometimes, however, the enzymes convert a harmless substance into a reactive form. For example, CYP-mediated oxidation often results in the generation of more reactive intermediates. Thus, many compounds that elicit toxic injury to the lung are not intrinsically pneumotoxic but cause damage to target cells following metabolic activation. A classic example of this is the activation of benzo(a)pyrene, which is a constituent of tobacco smoke and combustion products, and is... 

While the demonstration that the immune suppression by a given chemical is mediated by a metabolite, and not the parent compound, is an important observation, it does not in itself account for the mechanism of action. One indirect mechanism of action, which is consistent with a role for metabolism, involves a primary consequence of the generation of many reactive intermediates, that is, liver damage. Among many different types of adaptive responses, the liver is capable of secreting a number of soluble factors. Some of these soluble factors are capable of affecting immune responses. Most notably, as pointed out in Table 1, TGF- S is capable of modulating both T- and B-cell effector... 

The formation of reactive intermediates resulting from the metabolism of carbon disulfide by the hepatic MFO system may be involved in the hepatoxicity of this chemical. Pretreatment of rats with phenobarbital, an inducer of MFO activity, can enhance carbon disulfide-induced hepatotoxicity (Bus 1985). Inhibition of the MFO system might potentially reduce carbon disulfide-mediated hepatoxicity. In support of this possibility, Bond and De Matteis (1969) reported that pretreatment of rats with SKF-525A, an inhibitor of cytochrome P-450-mediated metabolism, reduced the liver damage from carbon disulfide in phenobarbital-pretreated animals. 

The mechanisms underlying hepatotoxicity from halothane remain unclear, but studies in animals have implicated the formation of reactive metabolites that either cause direct hepatocellular damage (eg, free radical intermediates) or initiate immune-mediated responses. With regard to the latter mechanism, serum from patients with halothane hepatitis contains a variety of autoantibodies against hepatic proteins, many of which are in a trifluoroacetylated form. These trifluoroacetylated proteins could be formed in the hepatocyte during the biotransformation of halothane by liver drug-metabolizing enzymes. However, TFA proteins have also been identified in the sera of patients who did not develop hepatitis after halothane anesthesia. 

---