drug metabolism

1. FACTORS THAT AFFECT DRUG
METABOLISM
DR O.A. ADESANOYE
BIC 703

2. METABOLISM
• Metabolism is the whole range of biochemical processes that
occur within a living organism. Metabolism consists of
anabolism (the buildup of substances) and catabolism (the
breakdown of substances). The term metabolism is commonly
used to refer specifically to the breakdown of food and its
transformation into energy (and some other substance).
• "Drug biotransformation, generally into more polar compounds
readily excreted from the body through urine or feces.“
• Drug metabolism is the term used to describe the
biotransformation of pharmaceutical substances in the body so
that they can be eliminated more easily. The majority of
metabolic processes that involve drugs occur in the liver, as the
enzymes that facilitate the reactions are concentrated there.

3. DRUG METABOLISM (BIOTRANSFORMATION)
• Drug metabolism is the metabolic breakdown of drugs by living
organisms, usually through specialized enzymatic systems.
• More generally, xenobiotic metabolism (from the Greek xenos
"stranger" and biotic "related to living beings") is the set of
metabolic pathways that modify the chemical structure of
xenobiotics, which are compounds foreign to an organism's
normal biochemistry, such as any drug or poison.
• These pathways are a form of biotransformation present in all
major groups of organisms, and are considered to be of ancient
origin. These reactions often act to detoxify poisonous
compounds (although in some cases the intermediates in
xenobiotic metabolism can themselves cause toxic effects).
• The study of drug metabolism is called pharmacokinetics

4. PHARMACOKINETICS
• Pharmacokinetics can be defined as the study of the time
course of drug absorption, distribution, metabolism, and
excretion.
• Absorption – the process of a substance entering the blood
circulation.
• Distribution – the dispersion or dissemination of substances
throughout the fluids and tissues of the body.
• Metabolism (biotransformation, or activation/inactivation)
– the recognition by the organism that a foreign substance is
present and the irreversible transformation of parent
compounds into metabolites / intermediates.
• Excretion – the removal of the substances from the body. In
rare cases, some drugs irreversibly accumulate in body
tissue.

7. DRUG
• A drug is any substance (with the exception of food and water) which,
when taken into the body, alters the body’s function either physically
and/or psychologically. Drugs may be legal (e.g. alcohol, caffeine and
tobacco) or illegal (e.g. cannabis, cocaine, ecstasy (MDMA) and heroin).
• A drug is any substance (other than food that provides nutritional
support) that, when inhaled, injected, smoked, consumed, absorbed via
a patch on the skin, or dissolved under the tongue causes a temporary
physiological (and often psychological) change in the body.
• In pharmacology, a drug is a chemical substance of known structure,
other than a nutrient of an essential dietary ingredient, which, when
administered to a living organism, produces a biological effect.
• A pharmaceutical drug, also called a medication or medicine, is a
chemical substance used to treat, cure, prevent, or diagnose a disease
or to promote well-being.

8. DRUG
• Natural or synthetic substance which (when taken into a living
body) affects its functioning or structure, and is used in the
diagnosis, mitigation, treatment, or prevention of a disease or
relief of discomfort. Also called legal drug or medicine. A legal
or medicinal drug (such as amphetamines), however, can be
harmful and addictive if misused (Not all medicines are safe).
• Habit forming stimulant or narcotic substance (such as alcohol,
cannabis, nicotine, or a derivative of cocoa or poppy) which
produces a state of arousal, contentment, or euphoria.
Continued or excessive use (called drug abuse or substance
abuse) of such substances causes addiction or dependence.
• Traditionally, drugs were obtained through extraction from
medicinal plants, but more recently also by organic synthesis.
Pharmaceutical drugs may be used for a limited duration, or on a
regular basis for chronic disorders

9. DRUG METABOLISING ENZYMES (DMEs)
• Drug metabolizing enzymes ( DMEs) are a diverse group of
proteins that are responsible for metabolizing a vast array of
xenobiotic chemicals, including drugs, carcinogens, pesticides,
pollutants, and food toxicants, as well as endogenous
compounds, such as steroids, prostaglandins, and bile acids
• Xenobiotics, including drugs and environmental chemicals,
are metabolized by four different kinds of reactions:
oxidation, reduction, hydrolysis, and conjugation.
• The first three reactions (oxidation, reduction, and hydrolysis)
are often grouped together and called functionalization
(Phase I) reactions, and the conjugation reactions are called
Phase II reactions

11. Oxidation
Cytochrome P450 monooxygenase system
Flavin-containing monooxygenase system
Alcohol dehydrogenase and aldehyde dehydrogenase
Monoamine oxidase
Co-oxidation by peroxidases
Reduction
NADPH-cytochrome P450 reductase
Hydrolysis
Esterases and amidase
Epoxide hydrolase

13. DRUG METABOLISING ENZYMES (DMEs)
• Phase I reactions introduce or unmask a functional group
(e.g., -OH, -CO2 H, -NH2, or -SH) within a molecule to enhance
its hydrophilicity.
• It can occur through direct introduction of the functional
group (e.g., aromatic and aliphatic hydroxylation) or by
modifying existing functionalities (e.g., reduction of the
ketones and aldehydes to alcohols; oxidation of alcohols to
acids; hydrolysis of ester and amides; reduction of azo and
nitro compounds; oxidative N - , O - , and S - dealkylation)
• Oxidative Phase I DMEs include cytochrome P450s (CYPs or
P450s), flavin-containing monooxygenases (FMOs),
monoamine oxidases (MAOs), and xanthine oxidase/aldehyde
oxidase ( XO/AO ).

14. DRUG METABOLISING ENZYMES (DMEs)
• Phase II biotransformation reactions include glucuronidation,
sulfonation, methylation, acetylation, amino acids (such as
glycine, glutamic acid, and taurine) and glutathione (GSH)
conjugations .
• The cofactors of these reactions react with functional groups
that are either present on the xenobiotics or are introduced
during Phase I biotransformation.
• Conjugative Phase II DMEs include uridine 5'-diphospho(UDP)-
glucuronosyltransferases (UGTs), sulfotransferases (SULTs),
glutathione S- transferases (GSTs), N-acetyltransferases (NATs),
and methyl (N-methyl-, thiomethyl-, and thiopurinemethyl-)
transferases.
• Conjugated metabolites are relatively more polar and hence are
readily excreted via urine or bile depending on the molecular
weight [MW] from the body.

15. DRUG METABOLISING ENZYMES (DMEs)
• Majority (>75%) of the top 200 marketed drugs are
eliminated by metabolism. Of the DMEs involved in the
metabolism of drugs, the dominant players are P450
enzymes, followed by UGTs and esterases.
• Together, these reactions account for ∼ 95% of the drug
metabolism. The other enzymes together metabolize only
∼ 5% of the marketed drugs
• Greater than 50% of drugs are failed in the Phase I clinical
trial due to toxicity or poor pharmacokinetics.
• Even after a drug is marketed there is a possibility that the
drug is either withdrawn from the market or acquires a
warning label (black box) due to some adverse drug
reactions, which were not seen in earlier clinical trials.

16. DRUG METABOLISING ENZYMES (DMEs)
• This is primarily due to species-related differences in the
expression, activity, inhibition, induction, pharmacogenetics,
and regulation of DMEs.
• Many of the DMEs exhibit genetic polymorphism and can be
inhibited or induced by the co-administered drugs and or/diet,
which can alter their catalytic activity or levels of expression.
• Nuclear receptors such as aryl hydrocarbon receptor (AhR),
pregnane X receptor (PXR), and constitutive androstane
receptor (CAR) together are believed to play a critical role in the
regulation of the catalytic activity of DMEs.
• In addition, the expression and activity of DMEs in humans are
markedly influenced by various other factors such as chronic
disease conditions, age, and hormonal variations during
pregnancy and environment

18. FACTORS THAT AFFECT DRUG METABOLISM

19. FACTORS THAT AFFECT DRUG METABOLISM
1.Physiological Conditions (age, diet, hormone balance)
2. Pathological Conditions (impaired liver or kidney function)
3. Genetic Factors (species/strain difference, sex/gender, ethnic
polymorphism, individual differences (enterohepatic circulation, nutrition,
intestinal flora))
4. Drug-drug Interactions (enzyme inhibition, enzyme induction)
5. Stereochemistry (substrate stereoselectivity, product stereoselectivity,
regioselectivity)
6. Environmental (diet, pesticides, heavy metals, air/industrial pollutants)
7. Route of administration
8. Drug dose/concentration, substrate competition, degree of protein
binding.

20. EFFECT OF AGE ON DRUG METABOLISM
• At the extremes of life - neonatal and geriatric, drug clearance can
be significantly different from the rest of humanity.
• Neonates (less than four weeks old) cannot clear certain drugs due
to immaturity of drug metabolizing systems.
• The elderly on the other hand cannot clear the drugs due to loss of
efficiency in their metabolizing systems (drug metabolism
diminishes with old age).
• Either way, the net result can be toxicity due to drug accumulation.
• Effect of age on drug metabolism is observed in both phase I
(oxidation) and phase II (conjugation) stages of metabolism.
• There is overlapping effects of other factors such as gender, strain
and hormones on influence of age on drug metabolism.

21. EFFECT OF AGE ON DRUG METABOLISM - ELDERLY
• The two main routes by which drugs are eliminated from the body are:
– Metabolism by liver enzyme
– Excretion by the kidneys
• Several age related changes are known to influence liver function which
include:
– Reduction in total liver size
– Reduction in liver blood flow (40-50% reduction between 25 and 65 years of age)
• The reduction in total liver size would result to a decrease in the levels of
drug metabolizing enzymes. A further decrease in efficiency would result in
the reduction in liver blood flow and this would result in a decrease of
exposure of the drug to metabolizing enzymes.
• The total size of the kidneys decrease with age, as does the number of
functioning nephrons. There is also decreased renal blood flow with
increasing age which will result in a progressive decrease in renal function.
• By the age of 70, both renal blood flow and the GFR would have decreased
on average by about 35%.

22. EFFECT OF AGE ON DRUG METABOLISM - ELDERLY
• Also, in older people, renal clearance is frequently aggravated by the
effects of enlarged prostate or chronic urinary tract infection. Acute
illness may lead to rapid reduction in renal clearance, especially if
accompanied by dehydration.
• It is common for multiple medical conditions to be present in older
patients which can lead to a greater potential for medication problems
due to polypharmacy.
• Prolonged plasma half-lives of drugs that are metabolized totally or
mainly by hepatic microsomal enzymes (e.g., acetaminophen,
antiarrhymics, anticonvulsants, antidepressants, antipsychotics,
benzodiazepines, indomethacin, theophylline, warfarin, some beta
blockers).
• In evaluating the effect of age on drug metabolism, one must
differentiate between "normal" loss of enzymatic activity with aging and
the effect of a diseased liver from hepatitis, cirrhosis, or decreased renal
function.

23. EFFECT OF AGE ON DRUG METABOLISM - NEONATES
• In most fetal and newborn animals, undeveloped or
deficient oxidative and conjugative enzymes are chiefly
responsible for the reduced metabolic capability seen.
• Infants carry much lower capacity of oxidation (CYP 450)
and conjugation (UGT) compared to adults. The capacity
generally approaches adult level after 1-2 months. Still,
extra caution is needed for babies under 2 years old.
• When hexobarbital at a dose of 10 mg/kg of body weight is
administered, newborn mouse sleeps more than 6 hours
while the adult mouse sleeps for fewer than 5 minutes
when given the same dose.

24. EFFECT OF AGE ON DRUG METABOLISM - NEONATES
• Oxidative (CYP) metabolism of tolbutamide appears to be
markedly lower in newborn with half-life of 40 hours
compared with the half-life of 8 hours in adults.
• Poor glucuronidating ability because of a deficiency in
glucuronyltransferase activity led to inability of infants to
conjugate chloramphenicol with glucuronic acid. This is
responsible for the accumulation of toxic levels of this
antibiotic, resulting in gray baby syndrome.
• Similarly, neonatal hyperbilirubin-emia (or kernicterus)
results from the inability of newborn babies to
glucuronidate bilirubin.
• Administration of Diazepam in infants may also result in
floppy baby syndrome in which flaccidity of baby is seen.

27. EFFECT OF AGE ON DRUG METABOLISM
• The effect of age on drug metabolism in relation to four
drugs: caffeine (CYP1A2), midazolam (CYP3A4), morphine
(glucuronidation) and paracetamol (glucuronidation and
sulphation) have been well studied.
• All the four drugs clearance are significantly reduced in the
neonatal period. This reduced clearance remains present in
infants and children under the age of two years for caffeine,
midazolam and morphine but not for paracetamol.
• There is considerable inter-individual variation in clearance
values for all ages and this appears to be greatest for
midazolam. For children aged two years and older the
median plasma clearance values for all four drugs are
similar to adolescents and adults.

28. SPECIES AND STRAIN DIFFERENCES
• The metabolism of many drugs and foreign compounds is often
species dependent. Different animal species may biotransform a
particular xenobiotic by similar or markedly different metabolic
pathways.
• Even within the same species, individual variations (strain
differences) may result in significant differences in a specific
metabolic pathway.
• Species difference poses a big problem especially during new
drug development. A new drug application requires the
developer to account for the product in different species as it
moves from the site of administration to final elimination from
the body.
• It is difficult to find appropriate animal models for a disease. It is
even harder to find animal models that mimic human drug
metabolism.

29. FACTORS THAT AFFECT SPECIES DIFFERENCES
• Sizes
• Sensitivity
• Gut conditions/Gut microflora
• Half-life of drugs
• Drug absorption
• Hepatic potential for drug detoxification
• Drug ionization
• Dosage interval/frequency of drug administration

32. SPECIES AND STRAIN DIFFERENCES
• Species variation has been observed in many oxidative
biotransformation reactions. For example, metabolism of
amphetamine occurs by two main pathways:
• oxidative deamination: human, rabbit, and guinea pig
• aromatic hydroxylation: rat

33. SPECIES AND STRAIN DIFFERENCES
• In the human, phenytoin undergoes aromatic oxidation to yield
primarily (S)(-)-p-hydroxyphenytoin; in the dog, oxidation occurs to
give mainly (R)(+)-m-hydroxyphenytoin. The difference is not only
in the position (i.e., meta or para) of aromatic hydroxylation but
also in which of the two phenyl rings (at C-5 of phenytoin)
undergoes aromatic oxidation.

34. SPECIES AND STRAIN DIFFERENCES
• Species differences in many conjugation reactions are
caused by the presence or absence of transferase
enzymes involved in the conjugative process.
• For example, cats lack glucuronyltransferase enzymes and
therefore tend to conjugate phenolic xenobiotics by
sulfation.
• In pigs, the situation is reversed: pigs are not able to
conjugate phenols with sulfate (because of lack of
sulfotransferase enzymes) but appear to have good
glucuronidation capability.

35. SPECIES AND STRAIN DIFFERENCES
• Conjugation of aromatic acids with amino acids (e.g., glycine,
glutamine) depends on the animal species as well as on the substrate.
For example, glycine conjugation is a common conjugation pathway for
benzoic acid in many animals. In certain birds (e.g., duck, goose, turkey),
however, glycine is replaced by the amino acid ornithine
• Phenylacetic acid is a substrate for both glycine and glutamine
conjugation in humans and other primates. However,
nonprimates, such as rabbit and rat, excrete phenylacetic acid
only as the glycine conjugate.
• The metabolism of the urinary antiseptic, phenazopyridine
(Pyridium) depends strongly on the animal. The diazo linkage
remains intact in over half of the metabolites in humans, whereas
40% of the metabolites in the guinea pig result from its cleavage.
The metabolic product pattern in human or guinea pig does not
correlate with that of either rat or mouse

38. HEREDITARY OR GENETIC FACTORS
• Marked individual differences in the metabolism of several drugs
exist in humans. Many of these large differences are based
on/due to genetic or hereditary factors.
• Genetic factors appear to influence the rate of oxidation of drugs
such as isoniazide, phenytoin, phenylbutazone, dicumarol, and
nortriptyline. The rate of oxidation of these drugs varies widely
among different individuals.
• In general, individuals who tend to oxidize one drug rapidly are
also likely to oxidize other drugs rapidly. Numerous studies in
twins (identical and fraternal) and in families indicate that
oxidation of these drugs is under genetic control.
• Polymorphism is a genetic variation resulting in the occurrence
of several different forms or types of individuals among the
members of a single species.

39. HEREDITARY OR GENETIC FACTORS
• Many patients do not respond to codeine and codeine
analogs. Now, It has been realized that for such
patients, their CYP2D6 isozyme does not readily O-
demethylate codeine to form morphine.
• This genetic polymorphism is seen in about 8% of
Caucasians, 4% of African Americans, and less than
1% of Asians.
• Genetic polymorphism with CYP isozymes gives rise to
many of these observations.
• Isoniazid (INH) remains effective in many areas, but it
is toxic and has tendency to cause peripheral
neurotoxicity in others.

42. HEREDITARY OR GENETIC FACTORS
• Isoniazid and some acetylated metabolites can undergo further oxidation
themselves to form highly reactive cytotoxic and carcinogenic species.
Indeed, in recent years, acetylation has become intensively studied
almost entirely due to its role in the carcinogenic activation of aromatic
amines.
• Genetic factors or pertinently intra-species genetic variations are
responsible for alterations in drug dosage and/or drug effect. These may
be related to gene-related alterations in drug metabolism or alterations
in tissue/receptor sensitivity. These variations can lead to genetic
tolerance, intolerance or idiosyncratic-reactions in susceptible
individuals.
• Genetic tolerance renders individuals less responsive to normal/ or
higher dosage; intolerance makes individuals to respond excessively to
normal or lower dosage.
• Thus, individuals within a given species may react variably to drug effect
and drug dosage. These variations may pertain to breeds, races, strains
or even to some individuals in a given population.

47. GUT MICROFLORAL AND DRUG METABOLISM
• Gut microbiota (formerly called gut flora) is the name given
today to the microbe population living in our intestine
• Gut flora, or gut microbiota, or gastrointestinal microbiota, is
the complex community of microorganisms that live in the
digestive tracts of humans and other animals, including insects
• Our gut microbiota contains tens of trillions of microorganisms,
including at least 1000 different species of known bacteria with
more than 3 million genes (150 times more than human genes).
Microbiota can in total weigh up to 2 kg.
• One third of our gut microbiota is common/similar to most
people, while two thirds are specific to each one of us. In other
words, the microbiota in your intestine is like an individual
identity card.

51. GUT MICROFLORAL AND DRUG METABOLISM
• The gut microbiota is regarded as an indispensable “metabolic
organ” in regard to its critical functions in maintaining human
health and involvement in various diseases.
• The gut microbiota plays crucial roles in drug metabolism by
activating or inactivating the pharmacological property of drugs.
• The entire composition of human gut microbiota is highly
variable. This variation contributes to the interindividual
different responses toward drug therapy including drug-induced
toxicity and efficacy.
• The investigation and elucidation of gut microbial impacts on
drug metabolism and toxicity will not only facilitate the way of
personalized medicine, but also improve rational drug design.

52. OTHER BENEFITS OF GUT MICROFLORA
• Helps in the digestion of foods that the stomach and
intestine cannot cope with
• Transportation of vitamins, minerals and other
nutrients across the gut wall
• Helps in the synthesis/production of nutrients e.g
biotin, vitamins and some amino acids
• Supporting the immune system by preventing growth
of pathogenic microbes (controlling parasites)
• To chelate heavy metals in the system

53. GUT MICROFLORAL AND DRUG METABOLISM
• In the time past, extensive investigations on individually
different responses to identical drug therapy has been
largely focused on the host genetic background, while the
roles of gut microbiota were underestimated owing to the
complexity of gut microbiota and the difficulty in the culture
of gut bacteria in vitro.
• In recent years, the microbial genomics has progressed from
culture-dependent to culture-independent strategies (i.e.
metagenomics), which facilitates the identification of roles
of gut microbiota in diseases and drug metabolism.
• Now, a new term “pharmacomicrobiomics” has been coined
to denote the effects of gut microbiota variations on
pharmacokinetics and pharmacodynamics.

54. GUT MICROFLORAL AND DRUG METABOLISM

55. GUT MICROFLORAL AND DRUG METABOLISM

56. Hydrolysis of Sorivudine to BVU by gut Microflora

57. Deconjugation of SN-38 glucuronide to parent
drug by microbial metabolism

58. Dehydroxylation of L-DOPA to m-Tyramine and/or m-
Hydroxyphenylacetic acid by microbes in the gut

59. Deacetylation of Phenacetin to p-Phenetidine
by gut microbes

60. Hormonal control of drug metabolism

61. INDUCTION AND INHIBITION OF DRUG METABOLISM
• Enzyme induction is a process whereby enzyme
activity is enhanced due to increased enzyme
synthesis which is also regulated by gene expression.
• ”An adaptive increase in the metabolizing capacity of
a tissue” – an increase in the transcription and
translation of specific CYP isoforms which are the
most efficient metabolizers of that compound.
• Hepatic induction has the most significant clinical
impact than other tissues such as the lung, intestine
and the kidneys.

66. MECHANISM OF ENZYME INDUCTION
• The mystery in the induction of CYPs by drugs and other
chemicals is how the cell recognizes these inducers and
how the information is conveyed to the transcriptional
machinery.
• The mystery is unravelled by the knowledge and study of
cellular receptors which are classed as cytoplasmic
receptors and nuclear receptors.
• Cytoplasmic receptor complex is responsible for the
induction of CYPs 1A1, 1A2 and 1B1.
• Nuclear receptor complex is responsible for the induction
of CYPs 2Bs. 2Cs and 3As

67. CYTOPLASMIC RECEPTOR – AhR SYSTEM
• The cytoplasm of most cells has a receptor complex that
consists of four components:
– The aryl hydrocarbon receptor (AhR)
– Heat shock protein
– Co-chaprone p23
– An immunophilin called XAP2
• This complex is known to be responsible for the induction
of CYPs 1A1, 1A2 and 1B1.
• The mechanism was unravelled with the use of TCDD
(2,3,7,8-tetrachlorodibenzo-p-dioxin) also called dioxin – a
polychlorinated dibenzo derivative.
• It is an herbicide, it is carcinogenic, teratogenic and has half
live exceeding 10 years in man

69. CONTROL AND SIGNIFICANCE OF AhR SYSTEM
• The incidence of enzyme induction and the overall effect depends on:
– the type and availability of ligand (drug inducer)
– The degree of CYP induction
– The amount of carcinogenic specie/metabolite produced
– Detoxification of product of induction and the efficiency of DNA repair
mechanism
• CYPs 1A1 1A2 are thought to leak reactive oxygen species which
could lead to DNA damage e.g, the implication of CYP 1A1 induction
in the metabolism of smoking related nitrosamines has been
reported leading to DNA damage.
• Another example of toxicological consequence is shown in the non-
ciliated ‘clara’ cells of the lungs.
• Induction of CYP 1A1/1A2 by PAHs in tobacco leads to the
formation of reactive epoxides which attack DNA, forming adducts
which are covalently bound to DNA and are strongly linked with
lung carcinogenicity.

70. THE NUCLEAR RECEPTOR SYSTEM
• This class of receptors control the induction of CYP 2Bs, 2Cs
and 3As.
• They are nuclear bound, hence the name.
• They bring about expression of CYPs and variety of proteins
induced by steroid hormones, vitamins, mineralocorticoids
and glucocorticoids.
• The major co-activator that regulate their action is the
hepatocyte nuclear proteins (HNFs). The most important is
HNF-4α.
• HNFs are found in many tissues but is more prominent in
the liver. It directly or indirectly regulates all endobiotic and
xenobiotic biotransformational processes.

71. FEATURES OF NUCLEAR RECEPTORS (NR)
• They are similar in structure, having N-terminal DNA
binding domain (DBD) and a C-terminal ligand binding
domain (LBD).
• Their ligands are small and lipophilic.
• NRs bind to DNA elements consisting of repeats of
hexamers in different kind of arrangements.
• There is tissue specificity of nuclear receptor giving rise to
tissue specificity drug induction.
• NR subfamilies which are closely related play key roles in
many P450-mediated physiological processes.
• They are controlled/regulated by master controlling
receptor known as hepatocyte nuclear factors (HNFαs).
• The NRs such as TR, VDR, CAR, and PXR form complexes
with RXR (Retinoic Acid Receptor) in order to bind HREs
(DREs). The presence of HNFαs is then required to make all
the binding processes productive and to activate gene
transcription.

72. THE NUCLEAR RECEPTOR SYSTEM
• Receptors under this class are:
• 1. Thyroid and Vitamin D receptors (TR and VDR)
• 2. Constitutive androstane receptors (CAR)
• 3. Pregrane X- receptor (PXR)
• 4. Chicken Xenobiotic receptor (CXR)
• Constitutive androstane receptors (CAR) will be
discussed here.

73. CAR-mediated
control of CYP
2 series and
CYP 3A

74. CAR-MEDIATED CONTROL OF CYP EXPRESSION
• This mechanism is under the control of HNF-4α and
glucocorticoid receptor.
• Substances required in CAR-mediated system
– CCRP – CAR retention protein
– HSP – Heat shock protein
– SRC-1 – steroid receptor co-activator-1
– RXR – Retinoic acid receptor
– ER6 – Everted Repeat element (DRE)
– PBREM – Phenobarbitone-responsive enhancer module (DRE)
– GRIP 1 – Glucocorticoid receptor interacting protein 1
• It is believed that the ligand interacts with the receptor by
dephosphorylating the receptor rather than full binding of
the inducer to CAR thereby stabilizing CAR throughout its
recruitment and binding processes of its co-activators.

75. CAR-MEDIATED CONTROL OF CYP EXPRESSION
• Some steroids such as progesterone and various androgens
can inhibit CAR action.
• CAR differs from AhR system in that it is semi-activated.
• It does not need to be stimulated into action by agonists as
it is already driving the expression and activity of CYPs and
conjugation system as well as transporter systems. The
presence of inducers only speeds up the process.
• It is likened to a throttle held half way down by itself
running the engine at half its capable number of revolution.
• Variation in CAR expression is one of the reason why there is
so much interindividual expression in biotransformation.

76. FACTS ON ENZYME INDUCERS

77. CHEMOPREVENTION BY PHASE II INDUCTION
• Cancer chemoprevention has been defined as the use of dietary
and pharmacological intervention with specific natural or
synthetic agents designed to prevent, suppress, or reverse the
process of carcinogenesis before the development of
malignancy.
• One of the major mechanisms of chemical protection against
carcinogenesis, mutagenesis, and other forms of toxicity
mediated by electrophiles is the induction of enzymes involved
in their deactivation, particularly phase II xenobiotic-
metabolizing enzymes such as glutathione S transferases (GSTs),
uridine diphosphate-glucuronosyl transferases (UGTs), and
NAD(P)H quinine oxidoreductase (NQO1).
• Indeed, induction of phase II enzymes can be achieved in many
target tissues by administering any of a diverse array of naturally
occurring and synthetic chemical agents.

78. INHIBITION OF DRUG METABOLISM
• Inhibition of drug metabolism represents a subject of great
interest
• For several reasons. It can give rise to a decrease in drug
biotransformation, low plasma levels, decreased clearance
(possibility of overdosing at common, therapeutic doses) and
increased risk in the occurrence of drug-drug interactions.
• Besides decreasing the therapeutic effect on one drug by
concurrent administration of another, it is unfortunately proven
that some drug-drug interactions may be even fatal;
• Practical aspects of inhibition include an understanding of the
phenomenon at the molecular level, especially as it relates both
to such drug –drug interactions (prediction, avoidance or
minimisation of the risks), as well as the utilisation of enzymes
as therapeutic targets.