2. • 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 .
3. • 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 auto-
induced metabolism of the drug exceeds the
rate at which new drug enters the body.
4. • Among these target genes are certain CYPs
and drug transporters.
• Thus, any drug that is a ligand for areceptor
that induces CYPs and transporters could lead
to drug interactions.
5. A list of ligands and the receptors (xenosensors)
through which they induce drug metabolism
6. 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.
7. 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.
8. 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
9. 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
10. The mechanism by which a drug may interact with nuclear receptors to
induce its own metabolism
11. 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-pregnane-
3,20-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 drugs-
acetaminophen, also function in the control of bilirubin
degradation, the process by which the liver decomposes
heme.
12. 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.
13. 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.
