Biotransformation of Toxicants

Virtually all chemicals that are ingested by animals undergo some chemical change or biotransformation. The biotransformation of chemicals generally leads to the formation of more polar metabolites that are more readily excreted. There are two types of biotransformation pathways, called phase I and phase II reactions. Phase I reactions include oxidations, reductions, and hydrolyses. Phase II reactions involve the conjugation of chemicals with hydrophilic moieties such as glutathione, glucuronides, sulfate, or amino acids. This chapter will provide an overview of the phase I and phase II reactions of toxic chemicals and discuss some of the important factors that can affect these reactions. Biotransformation modulates the biological effects of drugs and chemicals. Coadministration of two chemicals can result in exaggerated biological effects due to modulation of the metabolism of one compound by the other. These modulations can occur by inhibition of the biotransformation of the chemical or by induction of an increase in the enzyme system that metabolizes the chemical. Understanding the properties of the enzymes that catalyze biotransformation reactions is important for accurately predicting the outcomes of chemical metabolism and for effectively diagnosing the causes of adverse biological effects due to chemicals. Most enzymes behave in a systematic and predictable manner catalytically and kinetically. Phase I oxidations and reductions are primarily catalyzed by the cytochromes P450 and flavin-containing monooxygensases. Important phase II enzymes include glutathione S-transferase, glucuronosyl transferase, sulfotransferase, and acetyltransferase. Although the liver is the major site of xenobiotic bioactivation, extrahepatic metabolism plays a critical role in target organ toxicity. Various factors can modulate metabolism including enzyme induction, enzyme inhibition, diet, disease state, age, and gender. Polymorphisms have been identified in many of the enzymes involved in biotransformation. Therefore, it is extremely important to account for the potential effects of interindividual differences in xenobiotic metabolism on chemical toxicity in humans.