A new series of review articles on drug metabolizing enzymes: nomenclature of isoenzyme families, genetic organization, polymorphisms, substrate specificities, clinical relevance and role in carcinogenesis

Abstract

Predicting drug metabolism-dependent toxicity is of key importance in pharmacology and toxicology. The capacity for metabolic activation and inactivation strongly inXuences the toxic proWle of a substance as well as the shape of the dose–response curve (Hengstler et al. 2003; Bolt et al. 2004; Carmo et al. 2006, 2007). In recent years, metabolism has been one of the most active topics of our journal, including numerous contributions about induction or inhibition of xenobiotic metabolizing enzymes (Elovaara et al. 2007; Mitchell et al. 2007; Davila-Borja et al. 2007; Nannelli et al. 2007; Dorrenhaus et al. 2007; Ito et al. 2007; Becker et al. 2006; Bernshausen et al. 2006; Fatemi et al. 2006), metabolically competent cell systems, especially hepatocytes (Thum and Borlak 2007; Parody et al. 2007; Kurebayashi and Ohno 2006; Hewitt et al. 2007), diVerences in metabolic capacity between tissues and species (Myers and Spinnato 2007; Souma et al. 2006; Roos et al. 2006; Gultekin and Hicyilmaz 2007) and polymorphisms of drug metabolizing enzymes (Lin et al. 2007; Ulusoy et al. 2007; Kamimura 2006). A typical feature of drug metabolizing enzymes is large families of isoenzymes. An enormous diversity has evolved some 200–400 million years ago. This coincides with the period when some animals, such as initially amphibians and reptiles, moved from sea to land and started to eat plants. This led to a co-evolution of plants producing phytotoxins and animals responding with new detoxiWcation enzymes (Nebert et al. 1989). In recent years, much progress has been made in unraveling the enormous diversity of drug metabolizing enzymes. A second feature complicating research in drug metabolism is the high number of polymorphisms. Meanwhile, we know that our genome comprises approximately 3 million polymorphisms. The frequency of polymorphisms, mostly SNPs, of drug metabolizing enzymes usually is between 1 and 2 per 1000 nucleotides. Although much progress has been made, by far not all clinically relevant polymorphisms have been identiWed. Because of the dynamic progress in the Weld of drug metabolizing enzymes, the editors feel that a new series of review articles on drug metabolizing enzymes is required. Each review will focus on an individual family of isoenzymes and will focus on the following topics: