IDIOSYNCRATIC DRUG-REACTIONS - METABOLIC BIOACTIVATION AS A PATHOGENIC MECHANISM

The metabolism of drugs to chemically reactive metabolites may play a pivotal role in the pathogenesis of idiosyncratic drug toxicity. A lar ge number of in vitro studies and a limited number of in vivo studies have demonstrated that many drugs are not toxic per se, but produce to xicity after undergoing enzyme-mediated bioactivation to chemically re active species. Such reactive species may inflict a toxic insult on th e cell either directly or indirectly by acting as a hapten and initiat ing an immune-mediated reaction. The enzymes responsible for bioactiva tion have been widely studied, both quantitatively and qualitatively, the most important being the enzymes of the cytochrome P450 (CYP) mixe d function oxidase system. CYP enzymes are the most predominant drug m etabolising enzymes in the liver and are also present in most other ti ssues of the body. The diversity of this enzyme system means that a wi de range of xenobiotic substrates can be bioactivated by either a sing le CYP isoform or multiple isoforms of this enzyme superfamily. Other enzymes do, however, play an important role in drug bioactivation. In white blood cells, for example, myeloperoxidase has been shown to bioa ctivate a wide range of drugs. In other tissues low in CYP activity,pr ostaglandin H synthase may also be responsible for bioactivation; e.g. in the kidney paracetamol (acetaminophen) toxicity is thought to resu lt from activation via this enzyme. The phase II or conjugation enzyme s may also be important in the ultimate bioactivation of drug molecule s. Whilst activation by these enzymes is, to date, apparently confined to chemicals, most drugs are also substrates for these enzymes and bi oactivation by them must remain a possibility.