Xenobiotic Metabolism

Abstract

Humans are exposed continuously and unavoidably to a myriad of potentially toxic chemicals that are inherently lipophilic and, consequently, very difficult to excrete. To effect their elimination, the human body has developed appropriate enzyme systems that can transform metabolically these chemicals to hydrophilic, readily excretable, metabolites. This biotransformation process occurs in two distinct phases, Phase I and Phase II, and involves several enzyme systems, the most important being the cytochromes P450. The expression of these enzyme systems is regulated genetically but can be modulated also other factors, such as exposure to chemicals that can either increase or impair activity. Paradoxically, the same xenobiotic‐metabolizing enzyme systems also can convert biologically inactive chemicals to highly reactive intermediates that interact with vital cellular macromolecules and elicit various forms of toxicity. Thus, xenobiotic metabolism does not always lead to deactivation but can result also in metabolic activation with deleterious consequences.

Lc-MS-Based Metabolomics of Xenobiotic-Induced Toxicities

“…Xenobiotics can be either activated or detoxified by biotransformation reactions catalyzed by xenobiotic metabolizing enzymes (XME) in the body. The balance between bioactivation and detoxification, in many cases, may determine the toxic effects of xenobiotics [ 1 ]. Therefore, studying the biotransformation of xenobiotics in vivo is essential for understanding and predicting XIT.…”

“…2 ). It is known that major XMEs, including functionalizing (phase I) enzymes and conjugating (phase II) enzymes, have different roles in the bioactivation and detoxification of xenobiotics [ 1 ]. Animal models containing modified XME genes, such as mutation, knockout, or humanized models, have become powerful tools for investigating the role of XMEs in XIT [ 55 ].…”

“…Among these interactions, metabolic activities, which include both xenobiotic metabolism and endogenous metabolism, play central roles in determining the biological consequences of xenobiotic exposure, especially in xenobiotic-induced toxicities (XIT). Numerous toxicological studies have demonstrated that the formation of reactive metabolites and the disruption of endogenous metabolism are major contributors to the initiation and progression of XIT [ 1 , 2 ]. Therefore, examining metabolic events elicited by xenobiotic exposure is indispensable for studying the mechanisms of XIT.…”