Drug Biochemistry L2.pdf

© 2008 Society of Toxicology
BCHM 425:
DRUG BIOCHEMISTRY
Lecturer: S.I.R. Okoduwa, Ph.D.
•Department of Biochemistry,
Babcock University

Course Outlines
•2
• Xenobiotics metabolism;
• Biotransformation reactions (phase I & II);
• Toxicity and toxicology terms & concepts; dose-response curves;
• Classification of metabolites; microsomal and non-microsomal
enzyme systems; monooxygenases and mixed function oxidases-
cytochrome P450 family; induction and inhibition of drug
metabolism;
• Factors influencing drug metabolism;
• Mechanisms of drug toxicity;
• Theories of the mechanism of drug action.
• Drug resistance and factors affecting drug efficacy.
• The physiological and biochemical action of some selected drugs.
• Medicinal plants in the management and therapy of common
ailments- malaria, sickle cell anemia, common cold, hepatitis etc.

Toxicology Concepts

Risk
The likelihood of injury or
disease resulting from
exposure to a potential hazard
Evaluation of risk embodies all
the basic concepts of toxicology

The science of Toxicology helps people make
informed decisions and balance
RISKS vs. BENEFITS
The study found the
highest levels of
pesticide residues in
peaches, apples,
pears…….
AND Spinach.

Exposure
• Environmental, including
home and school
• Occupational
• Therapeutic
• Dietary
• Accidental
• Deliberate
Sources of exposure to
chemicals

Exposure
• In order for a chemical to produce a biological effect, it must first
reach a target individual (exposure pathway).
• Then the chemical must reach a target site within the body
(toxicokinetics).
• Toxicity is a function of the effective dose (how much) of a
foreign chemical (xenobiotic) at its target site, integrated over
time (how long).
• Individual factors such as body weight will influence the dose at
the target site
X =

Exposure
Route of Exposure
• The route (site) of exposure is an important
determinant of the ultimate dose—different
routes may result in different rates of
absorption.
– Dermal (skin)
– Inhalation (lung)
– Oral ingestion (Gastrointestinal)
– Injection
• The route of exposure may be important if
there are tissue-specific toxic responses.
• Toxic effects may be local or systemic

Exposure
Time of Exposure
• How long an organism is
exposed to a chemical is
important
Duration and frequency
contribute to dose. Both may
alter toxic effects.
– Acute Exposure = usually entails a
single exposure
– Chronic Exposures = multiple
exposures over time (frequency)

Father of Modern Toxicology
Paracelsus—1564
“All things are poisonous, only the dose makes it non-
poisonous.”
Dose alone determines toxicity
All chemicals—synthetic or natural—have the capacity
to be toxic
Dose
THE KEY CONCEPT in Toxicology

All Interactions between
chemicals and biological systems follow a
Dose-Response Relationship
Dose

SACRAMENTO, California—A woman
who competed in a radio station’s
contest to see how much water she
could drink without going to the
bathroom died of water intoxication,
the coroner’s office said Saturday.
Woman Dies after Water-drinking Contest: Water
Intoxication eyed in ‘Hold Your Wee for a Wii’ contest Death
Dose

• A key concept in Toxicology is the quantitative
relationship between the concentration of a
xenobiotic in the body and the magnitude of
the biological effect it produces.
• The magnitude of the effect of a xenobiotic is
usually a function of the amount of xenobiotic
to which a person is exposed (i.e., “The Dose
Makes the Poison”).
• In any given population, there will be a range
of sensitivities to a xenobiotic. It is extremely
useful to know what is the average sensitivity
of a population to a xenobiotic, and what the
average dose required to elicit a toxic response
will be.

Dose
• The magnitude of the toxic response is proportional
to the concentration (how much) of the chemical at
the target site.
• The concentration of a chemical at the target site is
proportional to the dose.
• Four important processes control the amount of a
chemical that reaches the target site.
– Absorption
– Tissue distribution
– Metabolism
– Excretion

Dose
Determines Whether a Chemical Will Be
Beneficial or Poisonous
Beneficial Dose Toxic Dose
Aspirin 300 – 1,000 mg 1,000 – 30,000 mg
Vitamin A 5000 units/day 50,000 units/day
Oxygen 20% (Air) 50 – 80% (Air)

Dose-Response Curves
“The Dose Makes the Poison”
0
1.0
Maximum Response
EC50
Arithmetic Scale
0 20 40 6080 100
Concentration
0.5
1.0
0
Maximum Response
EC50
Approx.
Linear
Range
0.1 1.0 10 100
Logarithmic Scale
0.5
Concentration
Rate
Threshold

“The Dose Makes the Poison”
Phenobarbital (mg/kg) Log Scale
ED50
LD50
Effective Dose Lethal Dose
100
60
80
40
20
100
60
80
40
20
10 20 30 50 100
1 2 3 5 7 10

Population Dose-Response
Mild Extreme
Many
Few
Number
of
Individuals
Response to SAME dose
Sensitive
Individuals
Maximal
Effect
Resistant
Individuals
Minimal
Effect
Majority of
Individuals
Average Effect

Too high: Anorexia,
anemia, nose bleeds,
muscle and joint pain
Some chemicals have both therapeutic
and toxic effects: Vitamin A
Dose
Adverse
response
Threshold
Too low:
Blindness,
dry skin,
increased
infections

Organs Respond to Chemicals in
Various Ways
Blood Organs
Desired Effects
Nutritive
Therapeutic
Undesired Effects
Toxic

Some Chemicals Are Transformed by
the Body (Metabolized) to Aid Excretion
Liver and other Organs
Detoxication
Less Toxic Metabolic Product
Liver
Feces / Bile
Lung
Kidney
Expired Air
Urine

Some Chemicals are Partially
Converted to Products that are More Toxic
than the Parent Substance
Liver and other Organs
Activation
More Toxic Metabolic Product

Toxicological Paradigm
Exposure
Internal
Dose
Biologically
Effective
Dose
Early
Biological
Effect
Altered
Structure &
Function
Disease
Absorption
Distribution
Metabolism
Excretion
Storage
Toxicokinetics Toxicodynamics
What We do to the Chemical What the Chemical Does to Us
Susceptibility and
Modifying Factors
(Genetics and Nutritional Status)

Biotransformation
Metabolism
• major mechanism for
terminating the biological
activity of chemicals
• frequently the single most
important determinant of the
duration and intensity of the
pharmacological response to a
chemical The LIVER is the
primary site of
metabolism
Liver
Biotransformation occurs in the
Liver, kidney, lung, gastrointestinal
track, and other organs

Pharmacogenetics of Metabolism
0 2 4 6 8 10 12
0
5
10
15
20
25
Response
Frequency
(#
of
individuals)
Plasma levels 6 hrs after oral dose
Fast Metabolizers
Harmful Side Effects
Slow Metabolizers
(elevated plasma levels)
Drug Concentration (g/mL)

The emerging field of
“Pharmacogenomics” or
“Toxicogenomics” offers
the potential to identify and protect
subsets of people predisposed to
toxicity from chemicals or drugs
Typical Population
Identify People with “normal” responses
More
Sensitive
Less
Sensitive

Tools of Modern Molecular Toxicology:
Genomics and Proteomics
NH2
NH2
NH2
-COOH
R
K -COOH
-COOH
K
+TO F MS: 24 MC A scans from Myo_tryptic.wiff M ax. 5191.0 co unts.
1000 1200 1400 1600 1800 2000 2200 2400 2600 2800 3000
m/z, am u
0
500
1000
1500
2000
2500
3000
3500
4000
4500
5000
5191
1360.7892
1606.8892
1938 .0629
1815.9397
1378.8696
2316.3092
1506.9692
1886.0672
1271.6925 1661.8925
1001.4584 1983.1071
1589.8688
1343.7703 1798.9216
1071.6147 2298.2643
1959.0339 2505.3460 2602.5045

THANK YOU

Drug Biochemistry L2.pdf

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