Xenobiotics enzyme induction

Intake of various xenobiotics such as phenobarbital, PCBs, or certain hydrocarbons can cause enzyme induction. It is thus important to know whether or not an individual has been exposed to these inducing agents in evaluating biochemical responses to xenobiotics. Metabolites of certain xenobiotics can inhibit or stimulate the activities of xenobiotic-metabolizing enzymes. 

Kong AN, Owuor E, Yu R, Hebbar V, Chen C, Hu R and Mandlekar S. 2001. Induction of xenobiotic enzymes by the MAP kinase pathway and the antioxidant or electrophile response element (ARE/EpRE). Drug Metab Rev 33(3-4) 255-271. 

There are many factors, both chemical and biological, which affect the disposition of xenobiotics. Chemical factors include size and structure, pKa, chirality, and lipophilicity. Biological factors include species, sex and strain, genetic factors, hormonal influences, disease and pathological conditions, age, stress, diet, dose, enzyme induction and inhibition, and tissue and organ specificity. All of these factors can affect the toxicity of a chemical by changing its disposition, especially its metabolism. 

Enzymes are extremely important because they must function properly to enable essential metabolic processes to occur in cells. Substances that interfere with the proper action of enzymes obviously have the potential to be toxic. Many xenobiotics that adversely affect enzymes are enzyme inhibitors, which slow down or stop enzymes from performing their normal functions as biochemical catalysts. Stimulation of the body to make enzymes that serve particular purposes, a process called enzyme induction, is also important in toxicology. 

Many inducers are substrates for the enzymes that they induce. From a teleological perspective, the purpose of enzyme induction is to foster clearance of xenobiotic chemicals from the body (the dioxin, TCDD, is a notable exception to this generalization). TCDD is a potent inducer of many DMEs that are regulated by the AHR (Table 3) however, TCDD is highly resistant to metabolism by any of the enzymes that it induces, particularly in... 

However, as summarized below, there are multiple and complex stages at which receptivity might be influenced. Much remains to be learned about specific genetic and non-genetic factors that govern individual sensitivity to enzyme induction by xenobiotics. 

Metabolic interactions resulting from concurrent detoxication of xenobiotics may modulate the activity of enzymes and thereby result in bioactivation reactions or a decrease in efficacy of a drug. The previous example of induction of CYP2E1 by ethanol and subsequent activation of acetaminophen to NAPQI is a case of metabolic interaction as well, where the mechanism is enzyme induction. 

Several factors can modulate the activity of xenobiotic-metabolizing enzymes, such as age, the nature of diet, and the presence of disease, but the most important appear to be genetic makeup and concurrent or prior exposure to chemicals (enzyme induction and enzyme inhibition). 

Key Words environmental regulation of xenobiotic metabolism, microsomal enzyme induction, activation of microsomal enzymes, drug-drug interactions, diet-drug interactions... 

Cigarette smoke is a powerful enzyme inducer. It has been shown to induce enzymes in the human placenta, an organ that is essentially inactive toward xenobiotics without induction. Cigarette smoke also lowers plasma levels of some drugs by inducing the enzymes that oxidize these. 

Some commercially available phenotyping kits use an array of coumarin analogs designed to be relatively isozyme-specific substrates (probes) that are metabolized to products with easily measurable spectral characteristics. Other commercially available kits use microsomes from baculovirus-infected cells that overexpress individual human GYP isoforms and fluorescent substrates (Vivid substrates) that can be incorporated into 1536 well formats. These simple systems do not readily lend themselves to the in vitro study of enzyme induction, however. The prediction of xenobiotic alteration of the expression of GYP activity in vivo from in vitro experiments will be discussed more completely in the chapter on drug—drug interactions. 

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