1 Multiple potentially harmful metabolites can be distinguished in the metabolic activation of halogenated benzenes: epoxides, phenols, benzoquinones and benzoquinone-derived glutathione conjugates.
2 The role of these (re-) active metabolites in the toxic effects induced by halogenated benzenes such as hepatotoxicity, nephrotoxicity, porphyria and thyroid toxicity is discussed.
3 Evidence is presented suggesting that the formation of reactive benzoquinone metabolites rather than the traditional epoxides is linked to halogenated benzene-induced hepatotoxicity.
4 A crucial role for the benzoquinone-derived glutathione adducts in halogenated benzene-induced nephrotoxicity is clearly established.
5 Although metabolic activation appears to be involved in porphyria, the nature of the ultimate porphyrinogenic metabolite has not been elucidated yet.
6 Disturbances in thyroid hormone (and retinoid) homeostasis can be (at least partially) explained by the formation of halogenated phenol metabolites.
7 In conclusion, for a relevant prediction of the ultimate fate of a compound in a living organism, one should know the chemical characteristics and reactivity of the parent compound and its metabolites, together with insight into the formation mechanism of each of the suspected metabolites, and an understanding of the interaction between a specific chemical (reactive) structure and its target molecule.
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