PROTEIN TARGETS OF XENOBIOTIC REACTIVE INTERMEDIATES

Many xenobiotics are metabolically activated to electrophilic intermed iates that form covalent adducts with proteins; the mechanism of toxic ity is either intrinsic or idiosyncratic in nature. Many intrinsic tox ins covalently modify cellular proteins and somehow initiate a sequenc e of events that leads to toxicity. Major protein adducts of several i ntrinsic toxins have been identified and demonstrate significant decre ases in enzymatic activity. The reactivity of intermediates and subcel lular localization of major targets may be important in the toxicity. Idiosyncratic toxicities are mediated through either a metabolic or im mune-mediated mechanism. Xenobiotics that cause hypersensitivity/autoi mmunity appear to have a limited number of protein targets, which are localized within the subcellular fraction where the electrophile is pr oduced, are highly substituted, and are accessible to the immune syste m. Metabolic idiosyncratic toxins appear to have limited targets and a re localized within a specific subcellular fraction. Identification of protein targets has given us insights into mechanisms of xenobiotic t oxicity.