1090-0233/01/030238 + 08 $35.00/0 © 2001 Harcourt Publishers Ltd INTRODUCTION The majority of xenobiotics (i.e. drugs, pesticides, carcinogens, food contaminants including toxins of vegetable or animal origin) which enter the an- imal body can undergo enzymic reactions known as ‘biotransformations’. As a result, the xenobiotic molecule generally becomes less lipophilic and more polar so that it may leave the body via the normal excretion routes. Whereas in the past the concept of biotrans- formation often implied detoxification, in recent years it has become apparent that this is not always the case. In certain instances biotransformation enzymes, through a process called ‘bioactivation’, may give rise to stable or unstable metabolic prod- ucts which are remarkably more toxic than the par- ent compounds. The consequences of metabolism on the biological activity of a given compound are depicted in Table I (Caldwell et al., 1988). Biotransformation reactions may also lead to the formation of reactive oxygen species or to changes in the normal levels of endogenous compounds (e.g. NADP/NADPH ratios, reduced glutathione, sulphate or amino acids used for conjugation). When reactive metabolites are formed, the tar- get of their toxic action(s) is dependent on their stability. Short-lived intermediates generally exert their toxicity in the tissue(s) where they are pro- duced, whereas stable ones may be formed in one Correspondence to: C. Nebbia, Department of Animal Pathology, Division of Pharmacology and Toxicology, University of Turin, Via Leonardo da Vinci 41, 10095 Grugliasco, Italy. Fax: +39 011 670 9017; E-mail: cnebbia@veter.unito.it Review Biotransformation Enzymes as Determinants of Xenobiotic Toxicity in Domestic Animals C. NEBBIA Department of Animal Pathology, Division of Pharmacology and Toxicology, University of Turin, Via Leonardo da Vinci 41, 10095 Grugliasco, Italy SUMMARY After coming in contact with living organisms, the majority of foreign compounds undergo a number of chemical reactions known as biotransformations. These are performed by hepatic and extra-hepatic enzyme systems and usually yield more polar derivatives, referred to as ‘metabolites’, which may leave the body via the urinary and biliary routes or be excreted in animal products such as milk and eggs. Biotransformation does not always imply detoxification because in certain instances metabolites will be produced that are cap- able of reacting with tissue macromolecules or acquiring toxic properties different to or greater than those of the parent molecule. In this review, which is focused on domestic animals, the role played by oxidative, reductive, hydrolytic and conjugative biotransformation enzymes in the activation/detoxification of xenobiotics is examined. The relationship between extra-hepatic metabolism and target organ toxicity as well as the action of rumen microflora on feed additives, phytotoxins, and pesticides are then discussed. Some of the most important metabolic-based species-related susceptibilities to different poisons, and the influence of enzyme inducers or inhibitors on xenobiotic toxicity and drug safety are also reviewed. KEY WORDS: Biotransformation enzymes; bioactivation; detoxification; domestic animals; xenobiotics. The Veterinary Journal 2001, 161, 238–252 doi: 10.1053/tvjl.2000.0561, available online at http://www.idealibrary.com on © 2001 Harcourt Publishers Ltd