MOLECULAR MECHANISM Retno Murwanti, D.V.M., M.SC., Ph.D.

Dept. of Pharmacology and Clinical Pharmacy

OF TOXICITY Faculty of Pharmacy,Universitas Gadjah Mada

2019

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MANIFESTATION OF THE TOXIC
EFFECT

u  direct toxic ac+on: +ssue lesions
u  pharmacological, physiological and biochemical
effects
u  teratogenesis
u  immunotoxicity
u  mutagenesis
u  carcinogenesis.

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 TOXIC RESPONSE DETECTION
Toxic responses may be the all-or-none type such as the death of the organism or they may be graded
responses.
Thus the main means of detec+on are:
u  Death: the LD50 assay has been u+lized as an indicator of toxicity
u  Pathological change
u  Biochemical change: this might involve an effect on an enzyme such as inhibi+on or altera+on in a
par+cular metabolic pathway. Alterna+vely the appearance of an enzyme or other substance in body
fluids may indicate leakage from +ssue due to damage and be indica+ve of pathological change;
u  Phsiological change: change in blood pressure, in temperature or in a response to a par+cular
s+mulus;
u  Changes in normal status: changes in body weight, food and water intake, urine output and organ
weight may all be sensi+ve indicators of either general or specific toxicity. These changes may of
course be confirmed by chemical, biochemical or histopathological measurements.
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WHY AN ORGAN MIGHT BE A TARGET ?
u its blood supply
u the presence of a par+cular enzyme or biochemical pathway
u the func+on or posi+on of the organ
u the vulnerability to disrup+on or degree of specializa+on
u the ability to repair damage
u the presence of par+cular uptake systems
u  the ability to metabolize the compound and the balance of toxica+on/
detoxica+on systems
u binding to par+cular macromolecules.
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 LIVER as a target organ of drug’s toxicity
1.  The large and diverse metabolic capabilities of the liver enable it to metabolize
many foreign compounds, but as metabolism does not always result in
detoxication this may make it a target.
2.  Has an extensive role in intermediary metabolism and synthesis and consequently
interference with endogenous metabolic pathways may lead to toxic effects.
3.  The secretion of bile by the liver may also be a factor, due to the biliary
excretion of foreign compounds leading to high concentrations, especially if
saturated as occurs with the hepatotoxic drug furosemide. Alternatively,
enterohepatic circulation can give rise to prolonged high concentrations in the
liver. Interference with bile production and flow as a result of precipitation of a
compound in the canalicular lumen or interference with bile flow may lead to
damage to the biliary system and surrounding hepatocytes.
4.  The blood supply ensures that the liver is exposed to relatively high
concentrations of toxic substances absorbed from the gastrointestinal tract.
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 SUSCEPTIBILITY OF THE LIVER
Factors contribute liver suscep+bility:
1.  First, most xenobio+cs enter the body through the gastrointes+nal (GI) tract
and, aRer absorp+on, are transported by the hepa+c portal vein to the liver:
thus the liver is the first organ perfused by chemicals that are absorbed in
the gut.
2.  A second factor is the high concentra8on in the liver of xenobio8c
metabolizing enzymes, primarily the cytochrome P450-dependent
monooxygenase system. Although most biotransforma+ons are detoxica+on
reac+ons, many oxida+ve reac+ons produce reac+ve metabolites that can
induce lesions within the liver. ORen areas of damage are in the centrilobular
region (higher concentra+on of cytochrome P450 in that area of the liver.
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Schematic of liver operational units, the classic lobule and the acinus. 7
TYPES OF LIVER INJURY

The types of injury to the liver depend on

u  the type of toxic agent,
u  the severity of intoxica+on, and
u  the type of exposure, whether acute or
chronic.

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TYPES OF HEPATOBILIARY INJURY

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CRITICAL FACTORS IN TOXICANT-
INDUCED LIVER INJURY
1.  Uptake and Concentra+on
2.  Bioac+va+on and Detoxifica+on
3.  Regenera+on
4.  Inflamma+on
5.  Immune Responses
6.  Idiosyncra+c Liver Injury
(a combina+on of gene defects and adverse events)
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KIDNEY as a target organ of drug’s toxicity
Factors Affecting the Susceptibility of the Kidney to Toxicants:
1.  High renal blood flow
2.  Concentration of chemicals in tubular fluid
3.  Reabsorption and/or secretion of chemicals through
tubular cells
4.  Activation of protoxicantsto reactive, and potentially toxic
metabolites

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STRUCTURE OF RENAL SYSTEM

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FUNCTION OF RENAL SYSTEM
T  he primary func+on : elimina+on of waste products, derived
either from endogenous metabolism or from the metabolism of
xenobio+cs.
  egula+on of body homeostasis, regula+ng extracellular fluid
R
volume, and elec-trolyte balance.
 synthesis of hormones that affect metabolism

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ACUTE KIDNEY INJURY
a  n abrupt decline in kidney func+on secondary to an injury
that leads to a func+onal or structural change in the kidney
  efined as a complex disorder that comprises mul+ple
d
causa+ve factors and occurs in a variety of se\ngs with
varied clinical manifesta+ons ranging from a minimal
eleva+on in serum crea+nine to anuric renal failure.
 Decrease of GFR (Glomerular filtra+on rate)

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Mechanisms that contribute to decreased GFR in acute renal failure.
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CHRONIC RENAL FAILURE
§  Progressive deteriora+on of renal func+on
may occur with long- term exposure to a
variety of chemicals
§  lithium, cyclosporine NSAIDs, lead, cadmium,
radiocontrast media, and an+-cancer agents

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BIOCHEMICAL MECHANISMS/MEDIATORS
OF RENAL CELL INJURY
1.  Cell Death
2.  Mediators of Toxicity
3.  Cellular/Subcellular and Molecular Targets
4.  Cell Volume and Ion Homeostasis
5.  Cytoskeleton and Cell Polarity
6.  Mitochondria
7.  Ca2+ Homeostasis
8.  Phospholipases
9.  Endonucleases
10. Proteinases Signaling Kinases
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 SITE-SELECTIVE INJURY
Many nephrotoxicants have their primary effects on discrete segment or regions of the
nephron.

For example, the proximal tubule is the primary target for most nephrotoxic antibiotics,
antineoplastics, halogenated hydrocarbons, mycotoxins, and heavy metals, whereas the
glomerulus is the primary site for immune complexes, the loop of Henle/collecting ducts for
fluoride ions, and the medulla/papilla for chronically consumed analgesic mixtures.

The reasons underlying this site-selective injury are complex but can be attributed in part to
site-specific differences in blood flow, transport and accumulation of chemicals,
physicochemical properties of the epithelium, reactivity of cellular/molecular targets, balance
of bioactivation/detoxification reactions, cellular energetics, and/or regenerative/repair
mechanisms.
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SUMMARY OF BIOTRANSFORMATIONAL TOXICITY
Liver/Kidney/Lung/Skin
Metabolizing Enzymes

LOCAL REACTIVE SPECIES

Covalent Binding

High Level, Low Level, Low Level,

Non-specific Highly-specific Non-specific

Phase II Immune
DNA Repair
sensitivity

Necrosis/ Cancer Immune

Organ Failure Response
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ASSIGNMENTS : ARTICLE, PPT
AND PRESENTATION
1.  the hepatotoxicity of carbon 6.  the destruction of nerve terminals
tetrachloride by 6-hydroxydopamine.
2.  the hepatotoxicity of white 7.  Lung adenocarcinoma by
phosphorus, benzo[a]pirene
3.  the hepatotoxicity of
acetaminophen 8.  Toxicity of vinyl chloride
4.  the pulmonary damage caused 9.  The nephrotoxicity of
by paraquat, Gentamycin
5.  the destruction of pancreatic 10. The nephrotoxicity of NSAID
cells by alloxan
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