Do Cytochrome P450 Enzymes Contribute to the Metabolism of Xenobiotics in Human?

Abstract

The cytochromes P450 (CYP) comprise a large multigene family of hemethiolate proteins which are of considerable importance in the metabolism of xenobiotics and endobiotics. CYP enzymes in humans as well as in other species have been intensively studied during recent years (Pelkonen et al., 2008; Turpeinen et al., 2007). It is possible to characterize metabolic reactions and routes, metabolic interactions, and to assign which CYP is involved in the metabolism of a certain xenobiotic by different in vitro approaches (Pelkonen et al., 2005; Pelkonen & Raunio, 2005; Hodgson and Rose, 2007a). Risk assessment needs reliable scientific information and one source of information is the characterization of the metabolic fate and toxicokinetics of compounds. Toxicokinetics refers to the movement of a xenobiotic into, through, and out of the body and is divided into several processes including absorption, distribution, metabolism, and excretion (ADME). Metabolism is one of the most important factors that can affect the overall toxic profile of a pesticide. During metabolism, the chemical is first biotransformed by phase I enzymes, usually by the cytochrome P450 (CYP) enzyme system, and then conjugated to a more soluble and excretable form by phase II conjugating enzyme systems (Guengerich & Shimada, 1991). In general, these enzymatic reactions are beneficial in that they help eliminate foreign compounds. Sometimes, however, these enzymes transform an otherwise harmless substance into a reactive form – a phenomenon known as metabolic activation (Guengerich & Shimada, 1991).Exposure to pesticides is a global challenge to risk assessment (Alavanja et al., 2004; Maroni et al., 2006). On a world-wide basis, acute pesticide poisoning is an important cause of morbidity and mortality. In an extrapolation, WHO/UNEP estimated that more than 3 million people were hospitalized for pesticide poisoning every year and that 220 000 died; it particularly noted that two-thirds of hospitalizations and the majority of deaths were attributable to intentional self-poisoning rather than to occupational or accidental poisoning (Konradsen et al., 2005; WHO/UNEP, 1990). Humans are inevitably exposed to pesticides in a variety of ways: at different dose levels and for varying periods of time (Boobis et al., 2008; Ellenhorns et al., 1997).