MECHANISMS

OF TOXICITY

EXCRETION
VERSUS
REABSORPTION

EXCRETION
It is the removal of xenobiotics from the
blood and their return to the external
environment

ELIMINATION FOR NONVOLATILE,

HYDROPHILIC CHEMICALS
Renal glomeruli <60 kDa
Proximal renal tubular cells and hepatocytes
transport chemicals from blood into renal tubules and
bile canaliculi
Renal transporters affinity for smaller (<300 Da)
Hepatic transporters affinity for larger (>400
Da)

LESS COMMON EXCRETORY

MECHANISMS:
DIFFUSION AND PARTITION ON THE EXCRETA
based on their (1) lipid content (2) acidity
Examples
Morphine transferred into milk
Amphetamine transferred into gastric juice

ROUTE AND SPEED OF

EXCRETION
It depends on the physicochemical
properties of the toxicant
Major excretory organs
Liver
Kidney

Efficiently remove highly

hydrophilic, ionized chemicals
(organic acids and bases)

REASONS
1. In the renal glomeruli, only compounds dissolved in
plasma water can be filtered.
2. Transporters (in hepatocytes and renal tubular cells)
are specialized for secretion of highly hydrophilic
organic acids and bases
3. Only hydrophilic chemicals are freely soluble in the
aqueous urine and bile
4. Lipid soluble compounds are readily reabsorbed by
transcellular diffusion

1.
2.
3.
4.

Plasma water
Transporters
Aqueous urine and bile
Lipid soluble compounds

ELIMINATION FOR
NONVOLATILE, HIGHLY
LIPOPHILIC CHEMICALS
Excretion by:
1. Mammary gland after the chemical is
dissolved in milk lipids
2. Bile in association with biliary micelles and
phospholipid vesicles
3. Intestinal excretion transport of chemical
from blood into lumen

ELIMINATION FOR VOLATILE,

NONREACTIVE CHEMICALS
Gases and volatile liquids
Diffuse from pulmonary capillaries
into the alveoli, and are exhaled

REABSORPTION

TUBULAR FLUID
REABSORPTION

Facilitates the delivery of toxicants by diffusing them back

across the tubular cells into the peritubular capillaries
It increases the intratubular concentration and residence
time by slowing urine flow
Depends on lipid-solubility of chemical

Weak organic acids (SP)

Salicylic acid
Phenobarbital
Weak organic bases (APQ)
Amphetamine
Procainamide
quinidine

 Acidification of urine
excretion of weak organic bases

Alkalinization of urine
excretion of weak organic acids

REABSORPTION OF
COMPOUNDS BY
TRANSPORTERS
Peptide transporters
B lactam antibiotics, ACE inhibitors
Physiologic anion transporters
metal oxyanions
Sulfate transporter
Chromate, molybdate
Phosphate transporter
- Arsenate

TOXICATION
VERSUS
DETOXICATION

TOXICATION
-It is the biotransformation to harmful products
-also known as Metabolic activation

ETHYLENE GLYCOL OXALIC ACID

- OA may cause acidosis and hypercalcemia
- may also cause obstruction of renal tubules
by precipitation as calcium oxalate

PARATHION PARAOXON

Paraoxon is a cholinesterase inhibitor

FLUOROACETATE FLUOROCITRATE

Rodenticide

Converted via citric acid cycle

Fluorocitrate is a fake substrate which inhibits aconitase

METHOXYLURANE RELEASE FLUORIDE

Results from CYP2E1-catalysed oxidation
Fluoride ion inhibits several enzymes (enolase), also
contrivutes to renal injury

CEPHALOSPORIN
Example: Cephoperazone
Cause hemorrhage due to release of 1-methyltetrazole-5-thiol
Inhibits vitamin K epoxide reductase (impairs activation of clotting
factors)

INCREASED REACTIVITY TOWARDS

ENDOGENOUS MOLECULES:
Formation of:
1. ELECTROPHILES contain electron-deficient atom with a
partial or full positive charge that allows it to react with electron
rich atoms in nucleophiles
2. FREE RADICAL a molecule or molecular fragment that
contains one or more unpaired electrons in its outer orbital
Formed by:
1.
2.
3.

Accepting an electron
Losing an electron
Homolytic fission of a covalent bond

FREE RADICAL
Accepting an electron
Paraquat
Doxorubicin
Nitrofurantoin
These xenobiotics accept electrons from reductases to give rise
to radicals

FREE RADICAL
2. Losing an electron
Nucleophilic xenobiotics

Phenols
Hydroquinones
Aminophenols
Aromatic amines (e.g. benzidine)
Hydrazines
Phenothiazines (e.g. Chlorpromazine)
Thiols

FREE RADICAL
3. Homolytic bond fission
-can be induced by electron transfer to the molecule
-involved in the conversion of CCl4 to trichloromethyl free radical
by an electron transfer fro CYP450

FENTON REACTION
Reductive homolytic fission of hydrogen
peroxide (HOOH) to HO and HO-

3. FORMATION OF
NUCLEOPHILES
-It is a relatively uncommon mechanism for activating toxicants
Examples:
Formation of CYANIDE from:
1. Amygdalin catalysed by bacterial B-glucosidase
2. Acrylonitrile after epoxidation and glutathione conjugation
3. Sodium nitroprusside by thiol-induced decomposition
Formation of CARBON MONOXIDE from:
. Dihalomethanes by oxidative dehalogenation

4. FORMATION OF REDOXACTIVE REACTANTS

Formation of methomoglobin-producing nitrite from

nitrate
Dapsone hydroxylamine
5-hydroxyprimaquine
Hydroxylated metabolites of respective metabolites
Produce methemoglobin by cooxidation

SUMMARY

Electron-deficient molecules most reactive metabolites

and molecular fragments such as
Electrophiles, neutral or cationic free radicals
Nucleophiles some are reactive, many are activated by
conversion to electrophiles
HCN, CO
Free radicals with extra electron cause damage by giving
rise to the neutral HO radical after the formation and
subsequent cleavage of HOOH

DETOXICATION

DETOXICATION
-It is the biotransformation that eliminates an ultimate
toxicant or prevents its formation
It may compete with toxication for a chemical

PATHWAYS OF
DETOXICATION
Toxicants without functional groups
detoxicated in 2 phases
(1) Addition of functional group to the
molecule
(2) Addition of endogenous acid to
functional group by transferase

 Nucleophiles detoxicated by conjugation

at the nucleophilic functional group
Hydroxylated compounds conjugated
by SGM (sulfation, glucuronidation,
methylation)
Thiols

MG
(methylation
and
glucuronidation)
Amines and hydrazines - acetylation

 Electrophiles A general mechanism for

detoxication is conjugation with thiol
nucleophile glutathione
Facilitated by glutathione-S-transferases
Ag, Cd, Hg, CH3Hg ions

 Free radicals Elimination of O2 is an important

mechanism because it can be converted into much
more reactive compounds by superoxide
dismutases (SOD), high capacity ensymes

 Protein toxins extra- and intracellular proteases

are involved in the inactivation of toxic polypeptides
Toxins found in venoms: contain intramolecular
disulfide bonds required for activity inactivated by
thioredoxin (endogenous dithiol protein that reduces
essential disulfide bond)
a and B bungaratoxin
Erabutoxin
phospholipase