N

Enzyme, transporter, signalling protein

Autologous protein

Teratogenicity | Carcinogenicity

I Apoptosis I 1 Hypersensitivity!

Figure 6.2. The role of metabolism in drug toxicity. A decrease in metabolism can lead to increased drug concentration and dose-dependent toxicity (which may also be due to cellular accumulation). The drug may undergo bioactivation to form chemically reactive metabolites, which if not adequately bioinactivated may bind to various cellular macromolecules, and lead to different forms of toxicity.

before it can initiate tissue damage. Indeed, it is possible that most therapeutically used drugs undergo some degree of bioactivation, but do not cause toxicity because the amount of toxic metabolite formed is below a "toxic" threshold or it is promptly detoxified. Both phase I and phase II enzymes can cause drug bioactivation, but in most cases it is the former, i.e. the cytochrome P450 enzymes, which are responsible (Pirmohamed et al, 1994).

Inadequate detoxication of a CRM is often the first step in the initiation of idiosyncratic drug toxicity (Park et al., 1992; Pirmohamed et al.,

1994). This may occur if there is an imbalance between drug bioactivation and bioinactivation pathways. Tissue-specific expression of enzymes involved in drug bioactivation and drug detoxica-tion may lead to a selective imbalance in that tissue resulting in tissue-selective toxicity (Park et al.,

1995). An imbalance may be the consequence of a genetically determined deficiency of an enzyme, or alternatively it may be acquired as a result of environmental factors such as infection, diet, or concomitant drug intake. It is important to note that inadequate detoxication of a CRM, although an important first step in the occurrence of toxicity, is not necessarily the ultimate step (Pirmohamed et al., 1996). Other factors, such as tissue repair enzymes, immune responsiveness and the biochemical processes that modulate tissue injury, may all serve as factors determining not only whether idiosyncratic toxicity occurs but also its severity.

An inadequately detoxified CRM can combine with or damage cellular macromolecules such as proteins and nucleic acids and result in various forms of toxicity, including teratogenicity, carci-nogenicity, cellular necrosis, and hypersensitivity (Park et al., 1995) (Figure 6.2). Binding of a CRM to nucleic acid may result in teratogenicity or carcinogenicity (Figure 6.2).

Binding to cellular macromolecules may result in either direct or immune-mediated toxicity (Pirmohamed et al., 1994) (Figure 6.2). With direct toxicity, binding of the CRM to a protein will interfere with its normal physiological function leading to cellular necrosis. Alternatively, the CRM can act as a hapten and initiate an immune reaction which may be due to a specific humoral (antibody) response, a cellular response (T lymphocytes), or a combination of both (Park et al., 1987, 1998, 2001; Pohl et al., 1988; Naisbitt et al., 2000a). The immune response can be directed against the drug (haptenic epitopes), the carrier protein (autoantigenic determinants), or the neoantigen created by the combination of the drug and the protein (new antigenic determinants). The factors that determine what type of toxicity is mediated by a CRM are poorly understood, but are likely to include the following (Gillette et al., 1984; Park et al., 1987; Boelsterli, 1993):

* the relative stability of the CRM, and thus its reactivity;

* the half-life of any drug-protein adducts which are formed and their concentration within the cell;

* the epitope density, i.e. the number of groups of the CRM which are covalently bound to a protein molecule; and

* the nature, physiological function, and subcel-lular site of the carrier protein to which the CRM binds.

In most cases, the differentiation between these two forms of idiosyncratic toxicity is largely empirical being based on symptomatology; for example, the occurrence of manifestations such as

Necrosis

Excretion rash, fever, lymphadenopathy, and eosinophilia all suggest drug hypersensitivity (Pessayre and Lar-rey, 1988; Pirmohamed et al, 1998). The lack of laboratory methodology by which to make a definitive diagnosis largely reflects our ignorance of the mechanism of toxicity in most cases of idiosyncratic toxiity.

PARACETAMOL: AN EXAMPLE OF A DRUG

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