Enzyme Induction | 7 Important points

 Enzyme Induction

This article outlines some key concepts related to Enzyme induction, its interplay with repression, and the interactions that can occur. This information can help you choose the best course of action. For more information, you can also check out our drug interactions section. It covers common drug interactions caused by Enzyme induction. After reading this article, you will be armed with the ability to make the best choice for your medication.

Enzyme induction

The term “enzyme induction” refers to a process by which a molecule induces the expression of an enzyme. The molecule may also inhibit the enzyme’s activity. The mechanisms of enzyme inhibition can be competitive, noncompetitive, or partially competitive. In addition, molecule induction can also be used to control gene expression. Both molecular biology and drug metabolism use induction in one form or another.

Induction in a hepatocyte may reflect the hepatic adaptation to chronic drug ingestion. This may be relevant to other drug-drug interactions that alter the metabolism of the targeted organ. A hepatocyte cultured at 37degC and 5% CO2 may be used as a preclinical model. Alternatively, induction studies are conducted using hepatocytes isolated from a single donor and evaluated using the MTS assay.

The most important mechanisms of DME induction are mediated by increased gene transcription and ligand-dependent activation of nuclear receptors. Aromatic hydrocarbon receptor, Pregnane X receptor, constitutive androstane receptor, and Peroxisome Proliferator Activator Receptor Alpha (PPAR-alpha) are some of the dominant receptors in the induction process. The CYPs are best characterized in terms of substrates, so enzyme induction is most commonly measured by measuring mRNA, protein, and enzymatic activity.

Enzyme Induction-Repression

Enzyme induction and repression are two major principles of genetic control of the activity of genes. Induction occurs when an enzyme is produced in response to a specific stimulus or condition. Repression occurs when repressor molecules prevent the manufacture of the enzyme. Both processes take place during gene transcription. Regulatory proteins are molecules that bind to DNA and enhance the function of RNA polymerase. Regulatory proteins may also act as repressors or activators.

Inducible operons include Lac and Trp, which encode enzymes required for lactose metabolism. Laci uses multiple operators to increase the efficiency of repression. Besides regulating lactose, riboflavin biosynthesis requires the oxidation of tryptophan. These two molecules also have a common co-repressor in the form of tryptophan.

Induction is a common mechanism for drug metabolism and involves increasing the activity of gene metabolizing enzymes and suppressing the activity of other genes. Drugs that induce enzyme induction include aminoglutethimide, barbiturates, carbamazepine, primidone, and griseofulvin. Other drugs, including ritonavir, are induced by certain drugs and vice versa.

Interactions Caused by Enzyme Induction

Drug interactions with CYP isoenzymes occur in a wide range of biological processes, and many of them are induced by enzyme induction. These interactions are insidious, as the induction occurs gradually and selectively. The result is an inability to counteract a particular drug’s effect on a different organ, which can cause adverse clinical outcomes. Such problems can be related to the loss of immunosuppressive or anticonvulsant efficacy and a lack of warfarin or oral contraceptive action. Further, failure to recognize the need to reduce a particular drug’s dosage can lead to bleeding.

Induced enzymes have varying pharmacological activity. Non-selective inducers act on a wide variety of CYP 450 families. Certain drugs, such as ethanol, can induce a specific isoenzyme. Inducing enzymes has important clinical consequences and occurs over a period of weeks. In general, induction effects may be detected within the first few days of treatment. Still, the reversibility of this effect depends on the time course of the drug’s administration.

Another drug that is susceptible to enzyme induction is irinotecan, a topoisomerase inhibitor primarily used to treat colon cancer. Irrespective of its mechanism, this drug is a prodrug that undergoes hydrolysis by carboxylesterases and glucuronidation by CYP3A4. St John’s Wort, a herbal supplement, reduces irinotecan’s availability by accelerating its clearance.

Enzyme induction and drug interactions

In addition to their effects on the metabolism of endogenous substrates, enzyme induction can lead to important drug interactions. The pharmacodynamic effects of drug-on-drug interactions can affect the pharmacokinetics of the metabolites. This process can alter the metabolism of vitamin D, extrahepatic enzyme systems, or a combination of these three. Enzyme-inhibiting agents, or those that inhibit the function of certain enzymes, include cimetidine, erythromycin, and isoniazid.

Enzyme Induction | 7 Important points

A wide range of drugs causes the induction of enzymes. Specific inducers are known to reduce the pharmacological activity of certain drugs. According to the Indiana University Department of Medicine, induction can occur with over 200 drugs. The inducing agent may also cause its biotransformation. The time course for enzyme induction varies depending on the specific drug. It may be as fast as two days after treatment, while its effects may last for weeks.

The mechanism of inhibition is less well understood. It may involve displacement of the victim drug from the plasma protein-binding sites. Displacement can result in a decrease in total plasma clearance. Displacement of enzymes can also cause the concentration of free compounds to increase to a hardly predictable level. This type of interchange can lead to the development of drug-induced liver dysfunction. The total plasma clearance of the victim drug decreases, and the free concentration tends to increase at a relatively slow rate.

Mechanism of Enzyme induction

Enzyme induction is an important metabolic control mechanism that increases the production of a specific enzyme upon exposure to a substrate. Inducible enzymes, like lactose cleavage and transport, are synthesized to respond to the presence of lactose. Inhibitors of enzyme induction are proteins that prevent the production of an enzyme unless a substrate is present. Normally, enzymes are inactive when no substrate is present, but this isn’t the case with enzyme induction.

Enzyme induction affects two kinds of enzyme systems in mammals: those expressed constitutively for basic life functions and those synthesized in response to xenobiotic stimuli. An enzyme is induced to increase activity in the drug-metabolizing enzyme. The pharmacological consequences of enzyme induction depend on where the enzyme is located, but the underlying cellular mechanisms are similar. In addition, many inducers also inhibit enzymes so that an inductive effect can be due to more than one mechanism.

Drugs like barbiturates induce the production of drug-metabolizing enzymes in rats. Induction varies according to the half-life of the drugs, so compounds with long half-lives and low metabolism rates are more likely to induce enzyme induction. Barbiturates with phenobarbitone and pentobarbitone are the most effective inducing agents, as they interact with cytochrome P-450. However, compounds with alkyl groups have a weaker inducing effect.

Importance of Enzyme induction

Induced enzymes are produced in the body by the pharmacological process. These enzymes include cytochromes P-450, NADPH-cytochrome P450 reductase, and cytochrome b5. Glucuronosyl transferases and glutathione transferases are also induced. Monooxygenases are also induced, but the degree of induction varies greatly.

Enzyme induction has traditionally been studied in drug development. Enzyme induction reduces the pharmacological activity of a variety of drugs. The Indiana University Department of Medicine provides examples of drug compounds that induce enzymes. Drugs that induce enzymes can also slowly develop tolerance. Pharmacokinetic tolerance is less noticeable than pharmacodynamic tolerance but is crucial for carbamazepine.

Induction can also change the proportions of isoenzymes in a tissue. For example, phenobarbital increases liver cytochrome P-450 concentrations threefold. Induced enzymes can increase activity 70-fold or more. Other enzymes, such as those in microsomes, can be induced with different compounds. Various types of inducers can have different effects on specific enzymes

Enzyme Assay | 8 Important points


Inducing an enzyme in a patient’s body is known as enzyme induction. It first appeared in 1954 when Brown et al. described the effects of rodent diets containing microsomal enzymes. They published their first review of microsomal enzyme induction in 1967. The induction effect is reflected in increased enzyme activity and reduced intrinsic metabolic clearance of drugs. This usually reduces the AUC, Cmax, and half-life of a drug.

The induction process can decrease the concentration of parent drugs at steady-state levels. Over time, the concentrations of the metabolites can rise or fall, depending on the inducing process. In addition, enzyme induction may cause the metabolite levels to increase or decrease. Thus, enzyme induction is a valuable tool for evaluating the potential effects of drug administration. But it should not be construed as a substitute for clinical trials.

Inducing the activity of a particular enzyme is a difficult task, as some compounds cause both induction and leakage of the enzyme. Therefore, enzyme induction in human volunteers may be difficult to distinguish from leakage of the same enzyme. Induced CYP enzymes are primarily responsible for CYP drug interactions. The following metabolites characterize the CYP enzymes involved in the metabolism of drugs in humans.

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