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• Xenobiotics can influence the extent of drug metabolism by activating transcription and inducing the expression of genes encoding drug-metabolizing enzymes. • Thus, a foreign compound may induce its own metabolism, as may certain drugs. • Consequence: A decrease in plasma drug concentration over the course of treatment, resulting in loss of efficacy, as the autoinduced metabolism of the drug exceeds the rate at which new drug enters the body.
• Several xenobiotic-biotransforming enzymes are inducible, :Expression can be increased (upregulated) usually in response to exposure to high concentrations of xenobiotics. • Induction is mediated by ligand-activated receptors : xenosensors; that are activated by xenobiotics (ligands) to DNA-binding proteins that upregulate the transcription of various genes encoding xenobiotic-biotransforming enzymes
• Especially cytochrome P450 (CYP) enzymes, which are induced to the greatest extent .
ENZYME INDUCTION • The induction (upregulation) of xenobiotic-biotransforming enzymes and transporters is a receptor-mediated, adaptive process that augments xenobiotic elimination during periods of high xenobiotic exposure. • It is not a toxicological or pathological response, but enzyme induction is often associated with liver enlargement (due to both hepatocellular hypertrophy and hyperplasia), and it may be associated with toxicological and pharmacological consequences, especially for the safety evaluation of drug candidates in laboratory animals and for clinical practice in humans. • In animals, enzyme induction may be associated with pharmacokinetic tolerance, whereby the xenobiotic induces its own elimination.
ENZYME INDUCTION…CONTD • Generally less important than enzyme inhibition because the latter can cause a rapid and profound increase in blood levels of a victim drug, which can cause an exaggerated pharmacological or toxicological effect. • In contrast, enzyme induction lowersblood levels, which does not cause an exaggerated Pharmacological or toxicological response to the drug. • However, May be associated with a loss of therapeutic effectiveness, which is a particular concern when it compromises the therapeutic effectiveness of drugs that have a narrow therapeutic index and are being used to treat a life-threatening illness, such as • anti-HIV drugs, antirejection drugs (like cyclosporine and tacrolimus), and oral anticoagulants (like warfarin), or when it is used with drugs that exhibit a quantal (all-or-nothing) dose–response relationship, such as oral contraceptive steroids (which either block or don’t block ovulation and thereby provide or don’t provide protection against unwanted pregnancy).
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ENZYME INDUCTION…CONTD CYP induction does not necessarily enhance the biotransformation of the inducer, in which case the induction is said to Be gratuitous Consequently, lack of autoinduction cannot be taken as evidence that a xenobiotic does not cause enzyme induction. For example, omeprazole induces CYP1A2, even though the disposition of this acid-suppressing drug is largely determined by CYP2C19 and, to a lesser extent, CYP3A4. Some of the most effective inducers of cytochrome P450 are polyhalogenated aromatic hydrocarbons (PHAHs), such as polychlorinated derivatives of dibenzo-p-dioxin (PCDDs), dibenzofurans (PCDFs), azobenzenes and azoxybenzenes, biphenyl (PCBs), and naphthalene. In general, highly chlorinated compounds are resistant to biotransformation and cause a prolonged induction of CYP and other enzymes.
ENZYME INDUCTION…CONTD • In general, CYP induction is mediated by four ligandactivated receptors, namely, AhR, CAR, PXR, and PPARα • These so called xenosensors resemble other nuclear receptors, such as steroid and thyroid hormone receptors, which has consequences for receptor interactions • Some xenosensors play in responding to endobiotics and regulating their metabolism (e.g., bilirubin, bile acids, and 1α,25-dihydroxyvitamin D3), and the role that some nuclear receptors (such as FXR, VDR, SHP, NF-κB) play in inducing or suppressing the expression of xenobiotic-biotransforming enzymes and transporters
A list of ligands and the receptors (xenosensors) through which they induce drug metabolism
Steps in CYP induction by Xenosensors
(1) Binding of ligand (xenobiotic) to the receptor,
which triggers conformational changes that promote its dissociation from accessory proteins (such as corepressors, chaperones, and cytoplasm-retention proteins) and/or promote its association with co-activators
(2) dimerization of the ligand-bound receptor with a partner protein to form a DNAbinding heterodimer (which is analogous to the two halves of a clothes peg coming together to form a functional unit) (3) translocation of the functional receptor heterodimer from the cytoplasm to the nucleus (4) binding of the functional receptor heterodimer to discrete regions of DNA (response elements) that are typically located in the 5-promoter region of the gene (which is analogous to a clothes peg being fastened to a clothes line)
(5) recruitment of other transcription factors and RNA-polymerase to form a transcription complex
(6) gene transcription, which leads to increased levels of CYP mRNA and CYP enzyme (as well as other xenobiotic-biotransforming enzymes and transporters).
THE ARYL HYDROCARBON RECEPTOR (AhR)
• Member of a superfamily of transcription factors with diverse roles in mammals: regulatory role in the development of the mammalian CNS and modulating the response to chemical and oxidative stress. • Per and Sim, two transcription factors involved in development of the CNS • Hypoxia-inducible factor 1α (HIF1α) that activates genes in response to low cellular O2 levels. • The AHR induces expression of genes encoding CYP1A1 and CYP1A2, two CYPs that are able to metabolically activate chemical carcinogens, including environmental contaminants and carcinogens derived from food.
Chemical carcinogens, including environmental contaminants and carcinogens derived from food. • Are inert unless metabolized by CYPs. • Thus, induction of these CYPs by a drug could potentially result in an increase in the toxicity and carcinogenicity of procarcinogens. • Eg: omeprazole, a proton pump inhibitor used to treat gastric and duodenal ulcers ;is a ligand for the AHR and can induce CYP1A1 and CYP1A2, with the possible consequences of toxin/carcinogen activation as well as drug-drug interactions in patients receiving agents that are substrates for either of these CYPs.
Type 2 nuclear receptors
• Same superfamily as the steroid hormone receptors. • On the basis of their structural similarity to steroid hormone receptors, (originally termed “orphan receptors,”) • Pregnane X receptor (PXR) • Constitutive androstane receptor (CAR • Peroxisome proliferator activated receptor (PPAR) • Subsequent studies revealed that some of these receptors are activated by xenobiotics, drugs
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PXR Activated by the synthetic steroid pregnane 16α-carbonitrile, is activated by a number of drugs including Antibiotics (rifampicin and roleandomycin) Ca2+ channel blockers (nifedipine), statins (mevastatin), antidiabetic drugs (troglitazone), HIV protease inhibitors (ritonavir), and anticancer drugs (paclitaxel). Hyperforin, a component of St. John’s wort, an over-the-counter herbal remedy used for depression, also activates PXR. This activation is thought to be the basis for the increase in failure of oral contraceptives in individuals taking St. John’s wort: Activated PXR is an inducer of CYP3A4, which can metabolize steroids found in oral contraceptives. Induces the expression of genes encoding certain drug transporters and phase 2 enzymes including SULTs and UGTs. Facilitates the metabolism and elimination of xenobiotics, drugs
The mechanism by which a drug may interact with nuclear receptors to induce its own metabolism
CAR : • CAR and PXR are closely related, activated by the same ligands and bind to the sameDNA-response elements • Ability to activate genes in the absence of ligand. • Steroid- androstanol; clotrimazole,meclizine are inverse agonists that inhibit gene activation by CAR
• Pesticide1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, steroid 5β-pregnane3,20-dione, -activate gene exp.when bound to CAR.
• Genes induced : encoding several CYPs (CYP2B6, CYP2C9, and CYP3A4), Phase 2 enzymes (GSTs, UGTs, and SULTs), and drug and endobiotic transporters. • CYP3A4 is induced by both PXR and CAR • Potential role in inducing the degradation of drugsacetaminophen, also function in the control of bilirubin degradation, the process by which the liver decomposes heme.
THE PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR (PPAR)
composed three members, α, β, and γ.
• PPARα is the target for the fibrate class of Hyperlipidemic drugs, : gemfibrozil and fenofibrate. • Activation of PPARα results in induction of target genes encoding fatty acid metabolizing enzymes that result in lowering of serum triglycerides • Induces CYP4 enzymes that carry out the oxidation of fatty acids and drugs with fatty acid–containing side chains, such as leukotriene and arachidonic acid analogs.
XENOSENSORS FACTORS • Certain xenosensors are activated by endogenous ligands (e.g. bilirubin, bile acids, and fatty acids activate CAR, PXR, and PPARα, respectively) • Certain nuclear receptors, such as the vitamin D receptor (VDR) can mimic PXR and induce CYP3A4, which inactivates the active metabolite of vitamin D. • Xenosensors are not just involved in xenobiotic disposition but also play a role in endobiotic homeostasis. • Induction is a pleiotropic response: Activation of AhR, CAR, PXR, PPARα, : result in alterations in the expression of numerous genes, some of which are upregulated (or induced) and some of which are downregulated (or suppressed). • Species differences also exist in the ligand specificities of these receptors. Eg: rifampicin (activates human PXR but not mouse/rat) • Meclizine ( activates mouse CAR but inhibits gene induction by human CAR. ) • Rodent model systems do not reflect the response of humans to drugs.
Induction of Drug Metabolising Enzymes
Several drugs and chemicals have ability to increase the drug metabolising activity of enzymes called as enzyme induction. These drugs known as enzyme inducers mainly interact with DNA and increase the synthesis of microsomal enzyme proteins, especially cytochrome P-450 and glucuronyl transferase. As a result, there is enhanced metabolism of endogenous substances (e.g., sex steroids) and drugs metabolised by microsomal enzymes. Some drugs (e.g., carbamazepine and rifampicin) may stimulate their own metabolism, the phenomenon being called as auto-induction or self induction.
Since different cytochrome P450 isoenzymes are involved in the metabolism of different drugs, enzyme induction by one drug affects metabolism of only those drugs, which are substrate for the induced isoenzyme.
However, some drugs like phenobarbitone may affect metabolism of a large number of drugs because they induce isoenzymes like CYP3A and CYP2D6 which act on many drugs.
Enzyme inducers are generally lipid-soluble compounds with relatively long plasma half-lives. Repeated administration of inducers for a few days (3 to 10 days) is often required for enzyme induction, and on stoppage of drug administration, the enzymes return to their original value over 1 to 3 weeks. Non-microsomal enzymes are not known to be induced by any drug or chemical.
In general, enzyme inducers are lipophilic at physiological pH and exhibit relatively long t 1/2 with high accumulation in the liver.
Different classes of enzyme inducers.
1. Barbiturates: Phenobarbitone, Phenobarbital.
2. Polycyclic aromatic hydrocarbons (PAH): 3methylcholanthrene (3-MC), 2,3,7,8,-tetrachlorodibenzo-p-dioxin
(TCDD), β-naphthoflavone β ( -NF).
3. Steroids: Pregnenalone 16-α -carbonitrile (PCN), Dexamethasone.
4. Simple hydrocarbons with aliphatic chains: Ethanol (chronic),
Acetone, 5. Hypolipidemic agents: Clofibrate, lauric acids.
6. Macrolide antibiotics: Triacetyloleandomycin (TAO).
Clinical importance of enzyme induction
It reduces efficacy and potency of drugs metabolised by these enzymes. It reduces plasma half-life and duration of action of drugs.
It enhances drug tolerance.
It increases drug toxicity by enhancing concentration of metabolite, if metabolite is toxic. It increases chances of drug interactions. It alters physiological status of animal due to altered metabolism of endogenous compounds like sex steroids.
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