Transcript Biotransformation Xenobiotic metabolism

Biotransformation
Xenobiotic metabolism
“Essentials of Toxicology”
Biotransformation
Biotransformation means chemical alteration of chemicals such
as nutrients, amino acids, toxins, xenobiotics or drugs in the
body. It is also needed to render nonpolar compounds polar so
that they are not reabsorbed in renal tubules and are excreted.
Biotransformation may results into Active
Inactive form
Active
Active or toxic form
Inactive
Active form
Unexcretable
Excretable form
Biotransformation
Results of biotransformation
more potent
active
active
Drug
or Poison
inactive
biotransformed
Drug or Poison
less potent
TOXIC
inactive
In general •nonsynthetic precede synthetic reactions
•nonsynthetic reactions can produce active metabolites
•synthetic reactions produce inactive metabolites
Biotransformation
Codeine
ACTIVE narcotic analgesic
H
N
Morphine
ACTIVE (more potent)narcotic analgesic
CH3
H
H
H3CO
Acety lsalicy lic Acid
ACTIVE analgesic
CO2H
OCCH3
O
O
N
CH3
H
OH
HO
Salicylic acid
ACTIVE analgesic
CO2H
OH
O
OH
Methanol
ACTIVE CNS depressant
CH3OH
Formaldehy de
TOXIC ()
HCH
O
Formic Acid
TOXIC ()
HCOH
O
Biotransformation
Why is Biotransformation necessary?
• Most drugs are excreted by the kidneys
• For renal excretion drugs should:
– have small molecular mass
– be polar in nature
– should be fully ionized at body pH
• Most drugs are complex and do not have these properties and thus
have to be broken down to simpler products.
Ctd…
Biotransformation
Pharmacologically active organic molecules tend to• Be highly lipophilic & remain unionized or partially ionized at
physiologic PH.
• Thus readily pass across biological barriers –membranes
• Strongly bound to plasma proteins
• Such substances are not readily filtered at the glomerulus.
• Their lipophilicity also facilitates to be reabsorbed through lipophilic
renal tubular membranes.
• This property also stops them from getting eliminated
• They have to be converted to simpler hydrophilic compounds so that
they are eliminated and their action is terminated.
Biotransformation
Ctd…
• Biotransformation can also result in bioactivation, which
involves the production of reactive metabolites that are
more toxic, mutagenic, or carcinogenic than their parent
compound(s).
• Drugs may converted to– less toxic materials
– more toxic materials
– materials with different type of effect or toxicity
Beside these, biotransformation is called a biochemical defense
mechanism as it handles different xenobiotics, drugs, toxicants,
body wastes (hemoglobin) or other unwanted substances to those
we get exposed.
Biotransformation
Where do biotransformations occur?
• Liver is the principal organ of drug metabolism although every
tissue has some ability to metabolize drugs.
• Other tissues that display considerable activity include the GIT,
the lungs, the skin, and the kidneys.
•Following oral administration, many drugs (e.g.
isoproterenol,morphine) absorbed intact from the small intestine
and transported first via the portal system to the liver, where they
undergo extensive metabolism ( first-pass metabolism).
• Some orally administered drugs (e.g.clonazepam, chlorpromazine)
are extensively metabolized in the intestine than in the liver.
Ctd…
Biotransformation
• Thus intestinal metabolism may contribute to the overall first-pass
effect.
• First pass effects may so greatly limit the bioavailability of orally
administered drugs.
•The lower gut harbors intestinal microorganisms that are capable
of many biotransformation reactions.
•Although drug biotransformation in vivo can occur by
spontaneous, noncatalyzed chemical reactions, the vast majority are
catalyzed by specific cellular enzymes.At the cellular level, these
enzymes may be located in the –
i) Endoplasmic reticulum ii) mitochondria iii) cytosol iii)
lysosomes iv) even the nuclear envelope or v) plasma membrane.
Biotransformation
• Water soluble xenobiotics are easier to eliminate in
urine, feces but not exhalation as t1/2 is low.
Lipophilic barbiturates such as thiopental & phenobarbital would have halflives greater than 100 years if they were not converted to water-soluble
compounds.
• Multiple enzymes (families)
–
–
–
–
–
Constitutively expressed
Inducible
Broad specificity
Polymorphic
Stereo-isomer specificity
Biotransformation
Potentially toxic xenobiotic
Detoxification
Inactive metabolite
Relatively harmless
Metabolic
activation
Reactive intermediate
Converting lipophilic to water
soluble compounds
Lipophilic
Xenobiotic
(non-polar)
Phase I - Activation
Reactive intermediate
Phase II - Conjugation
Conjugate
Excretion
Water soluble
(polar)
Phase I
• introduction of functional group
• hydrophilicity increases slightly
• may inactivate or activate original compound
• major player is CYP or mixed function oxygenase
(MFO) system in conjunction with NAD(P)H
• location of reactions is smooth endoplasmic reticulum
Phase II
• conjugation with endogenous molecules
(GSH, glycine, cystein, glucuronic acid)
• hydrophilicity increases substantially
• neutralization of active metabolic intermediates
• facilitation of elimination
• location of reactions is cytoplasm
Phase I reactions
 Oxidation
 Hydroxylation (addition of -OH group)
 N- and O- Dealkylation (removal of -CH side chains)
 Deamination (removal of -NH side chains)
 Epoxidation (formation of epoxides)
C
 Oxygen addition (sulfoxidation, N-oxidation)
 Hydrogen removal
 Reduction
 Hydrogen addition (unsaturated bonds to saturated)
 Donor molecules include GSH, FAD, NAD(P)H
 Oxygen removal
 Hydrolysis
C
O
 Splitting of C-N-C (amide) and C-O-C (ester) bonds
O
epoxide
C
Biotransformation
• Activation of xenobiotics is a key element
(e.g. benzene, vinyl chloride)
– Reactive intermediates include epoxides and free
radical species (unpaired electrons) that are short-lived
and hence highly reactive
– Protection is provided by
• endogenous antioxidant substances, e.g. GSH
• vitamins C and E
• antioxidant enzymes
Antioxidant molecules are oxidized in the process but have the
capacity to regenerate the reduced form from the oxidized NAD(P)H is a key player
Cytochrome P450 (CYP)
Mixed Function Oxidases (MFO)
•
•
•
•
•
Located in many tissues but highly in liver ER
Human: 16 gene families
CYP 1,2,3 perform drug metabolism
>48 genes sequenced
Key forms: CYP1A2, CYP2C9, CYP2C19,
CYP2D6, CYP2E1, and CYP3A4
• Highly inducible
– Alcohol
– Barbiturates
CYP2E1
CYP2B
CYPs are the major enzymes involved in drug metabolism, accounting
for ~75% of the total metabolism.Most drugs undergo deactivation by
CYPs, either directly or by facilitated excretion from the body. Also,
many substances are bioactivated by CYPs to form their active
compounds.
Proportion of drugs metabolized by different CYPs
Figure CYP450 Reaction
Sequence
OH
DRUG
DRUG
CYP450
Fe3+
CYP450
Fe3+
CYP450
Fe3+
DRUG
DRUG
NADPH +
OH
CYP450
Fe3+
H+
e-
CYP450
reductase
CYP450
Fe2+
NADPH + H+
DRUG
O
DRUG
H+
eH2O
CYP450
Fe2+
DRUG
DRUG
O21-
O2
CYP450
Fe2+
O2
Oxidation of vinyl chloride to an
epoxide
Metabolic enzymes
1.
Microsomal:
1.
2.
2.
Non-microsomal
1.
2.
3.
3.
CYP450 monooxygenases
Flavin monooxygenase
Alcohol dehydrogenase
Aldehyde dehydrogenase
Monoamine and diamine oxidases
Both
1.
2.
3.
Esterases and Amidases
Prostaglandin synthase
Peroxidases
Cooxidation of
acetaminophen
by prostaglandin
endoperoxide
synthetase
Hydrolysis of esters and amides
Hydrolysis of organophosphates
Hydrolysis of epoxides
Stereoselective
hydroxylation
Metabolism of
benzo(a)pyrene to
9,10 epoxide:
Potent mutagen
that binds DNA