Enzyme induction mechanism

D. C. Evans, D. P. Hartley, R. Evers (2001). Enzyme induction—Mechanisms, assays, and relevance to drug discovery and development. Ann. Rep. Med. Chem. 38 315. 

Fundamental models include cell dimensions, transport of substrates and metabolites across the cell membrane, and the elementary cell bioreaction steps and their corresponding enzyme induction mechanism. In recent years further kinetic steps have been added to the above models which are based on the conversion of substrates to metabolites. Thus the kinetics of protein synthesis by transcription and translation from the genome add much further complexity to cell kinetics. 

The interactions may be physicochemical without the participation of biological mechanisms for example, deep lung exposure to highly soluble irritative gases, such as sulfur dioxide, may become enhanced due to adsorption of the gas onto fine particles. Biological interactions may occur at all stages and body sites. For example, toxicity is increased when adverse effects are due to some reactive metabolic intermediate and exposure to another agent stimulates its metabolic activation (enzyme induction). 

As indicated above in the section on "Genotoxic Effects", it is likely that mirex and chlordecone are tumor promoters and not tumor initiators. Initiators irreversibly alter DNA by a mutation, chromosomal aberration, or other alteration. Promoters act by facilitating the proliferation of previously initiated preneoplastic cells. One of the mechanisms for promotion is believed to involve suppression of inhibitory proliferative control through inhibition of gap-junctional-mediated intercellular communication as well as enzyme induction (Trosko et al. 1983). The results of studies to evaluate the promotional activity potential of mirex in mice indicate that mirex is a mouse skin cancer promoter but exerts this toxicity through a hitherto unknown mechanism that is different from that of phorbol esters, such as TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). Unlike initiation, promotion is a reversible process to a point. This implies, at least in theory, that there may be justification for setting NOAELs for promoters. 

II.e. 5.2. Interactions between first and second generation AEDs. Felbamate raises plasma concentrations of phenytoin, valproic acid and carbamazepine. Clearance of tiagabine, topiramate and zon-isamide is increased in the presence of an enzyme inducer. Vigabatrin reduces phenytoin concentrations after 4-5 weeks of comedication (via an unknown mechanism). For tiagabine, the elimination half-life may be reduced by 2-3 hours in the presence of an enzyme-induction AED. Lamotrigine elimination is slower if given with valproic acid. Topiramate reduces elimination of phenytoin. 

Induction of drug-metabolizing activity can be due either to synthesis of new enzyme protein or to a decrease in the proteolytic degradation of the enzyme. Increased enzyme synthesis is the result of an increase in messenger RNA (mRNA) production (transcription) or in the translation of mRNA into protein. Regardless of the mechanism, the net result of enzyme induction is the increased turnover (metabolism) of substrate. Whereas one frequently associates enzyme inhibition with an increase in potential for toxicity, enzyme induction is most commonly associated with therapeutic failure due to inability to achieve required drug concentrations. 

C is correct, since the most common mechanism of enzyme induction is through synthesis of new enzyme protein, which does not occur immediately. Finally, mechanism-based inactivation (D) is also correct, since this is irreversible, leaving the enzyme inactive and eventually it is degraded by the body. 

Carbamazepine induces hepatic cytochrome P450 (CYP) enzymes, which may reduce levels of other medications. Through the mechanism of hepatic enzyme induction, carbamazepine therapy can lead to oral contraceptive failure therefore, women should be advised to consider alternative forms of birth control while taking carbamazepine. Similarly, use of medications or substances that inhibit CYP 3A3/4 (discussed in Chapter 1) may result in significant increases in plasma carbamazepine levels. 

Batt AM, Siest G, Magdalou J, et al. Enzyme induction by drugs and toxins. Clin Chem Acta 1992 209 109. Bresnick E, Houser WH. The induction of cytochrome P-450c by cytosolic hydrocarbons proceeds through the interaction of a 4S cytosolic binding protein. In Ruckpaul K, Rein H, eds. Frontiers of Biotransformation, Vol. II, Principles, Mechanisms and Biological Consequences of Induction. London Taylor Francis, 1990. 

Fibrates (such as clofibrate) are hypolipidemic drugs. They cause a number of biological and biochemical effects, including enzyme induction, peroxisomal proliferation, liver hypertrophy and hyperplasia, and liver cancer. The mechanism is believed to be mediated through the PPARa receptor. Animals lacking this receptor do not show these effects. 

Metabolism of antipsychotics is through two mechanisms conjugation with glucuronic acid and oxidation by hepatic microsomal enzymes. Both mechanisms of metabolism and subsequent inactivation take place in the liver. Some degree of enzyme induction may occur because of prolonged use of antipsychotics, which may be responsible for increasing the rate of metabolism of these drugs. 

PBPK models for 2,3,7,8-TCDD are discussed below. The pharmacokinetic behavior of 2,3,7,8-TCDD, especially distribution, has been shown to be dose-dependent and involves protein binding and enzyme induction in hepatic tissue. Thus, terms describing these interactions have been included in the animal models described below. Furthermore, since induction of these dioxin-binding proteins is a process mediated by the interaction of a dioxin-receptor (the Ah receptor) complex with specific binding sites on DNA additional terms were included in the models. For a detailed explanation regarding the Ah receptor and its involvement in the mechanism of action of 2,3,7,8-TCDD and structurally related halogenated aromatic hydrocarbons, see Section 2.4.2. 

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