Cytochrome P450 liver enzymes induction

Metabolism and drug-drug interaction issues are discovered by screening for inhibition and induction of cytochrome P450 liver enzymes (CYP450). FDA guidelines have specific recommendation for substrates (Table 7.2) and inhibitors (Table 7.3) to be nsed in these assays. 

For halogenated aromatic hydrocarbons like polychlorinated biphenyls (PCBs), polychlorinated dibenzofurans (PCDFs), and polychlorinated dibenzo-p-dioxins (PCDDs) the binding to the aryl hydrocarbon (Ah) receptor regulates their toxicity [89]. The Ah receptor controls the induction of one of the cytochrome P450 enzymes in the liver. Toxic responses such as thymic atrophy, iveight loss, immu-notoxicity and acute lethality are associated ivith the relative affinity of PCBs, PCDFs and PCDDs for the Ah receptor [89]. The quantitative structure-activity relationship (QSAR) models predicting the affinity of the halogenated aromatic hydrocarbons ivith the Ah receptor describe the electron acceptor capability as well as the hydrophobicity and polarizability of the chemicals [89[. 

In addition, many of the cytochrome P450 enzymes can be induced. Induction causes the liver to produce a greater amount of the enzyme, which can increase elimination and reduce plasma levels... 

The induction of liver enzymes has been demonstrated in many species, including humans, and probably represents a homeostatic, defense mechanism. Induction usually requires multiple exposures to the inducing agent over a period of several days, the time required for the synthesis of new protein. Enzymes induced include the cytochrome P450 monooxygenase system glucuronyltransferase the microsomal ethanol oxidative system and the steroid-metabolizing system. 

In adults, excessive alcohol consumption reduces liver reserves of vitamin A, both as a result of alcoholic liver damage and also by induction of cytochrome P450 enzymes that catalyze the oxidation of retinol to retinoic acid (as also occurs with chronic use of barbiturates). However, chronic consumption of alcohol can also potentiate the toxicity of retinol (Section 2.5.1). 

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