The use of stable isotopes to identify reactive metabolites and target macromolecules associated with toxicities of halogenated hydrocarbon compounds

Abstract

1. Halogenated compounds, such as the inhalation anaesthetics, halothane and enflurane, and the chemicals chloroform, carbon tetrachloride, and bromotrichloromethane can cause hepatotoxicity, nephrotoxicity, and inactivation of cytochromes P-450. Each of these toxicities is mediated by reactive metabolites.

2. Stable isotopes of hydrogen, carbon, chlorine and oxygen have been used in conjunction with mass spectrometry and n.m.r. spectrometry to identify the structures of these metabolites, to elucidate the mechanisms of their formation, and to characterize the structures of their macromolecular adducts.

3. In a number of cases, oxidative pathways of metabolism to toxic metabolites have been defined by kinetic deuterium isotope effects.

4. Recently, we have found that the trichloromethyl radical metabolite of bromotrichloromethane can activate myoglobin by causing the covalent cross-linking of haem to protein. The structure of a haem—myoglobin adduct has been defined by the use of stable isotope studies.