Target organ toxicity - Neurotoxicity Flashcards
What are the main means of detection / In vivo signs of toxicity?
- Death
LD50 - Pathological changes
Development of a tumor or destruction of tissue, but it would be detectable by observation either macroscopically or microscopically - Biochemical change
An effect on an enzyme such as inhibition or alteration in a particular metabolic pathway - Physiological change
A change in blood pressure, temperature, or in a response to a particular stimulus - Changes in normal status
Body weight, food and water intake, urine output, and organ weight may all be sensitive indicators of either general or specific toxicity
Why are the main reasons some organs are targets?
- Its blood supply – richly vascularised tissue
- The presence of a particular enzyme or biochemical pathway
- The function or position of the organ (GI, skin, lung) – may be exposed to higher concentrations of foreign compounds prior to dilution by blood and other fluids
- The vulnerability to disruption or degree of specialization (CNS, heart)
- The ability to repair damage
- The presence of particular uptake systems
- The ability to metabolize/biotransformate the compound and the balance of toxication/detoxication systems
- Binding to particular macromolecules
Why is the brain vulnerable?
- High energy requirement
- Complex geometry
- Little capacity to regenerate
Why is the heart vulnerable?
- Lacks enzymes involved in detoxication
What is the toxic mechanism of adriamycin/doxorubicin?
They are topoisomerase inhibitors used in treatment of cancer
–> risk - causes cumulative, dose-related cardiac damage
Mechanism: Accumulates in mitochondria due to binding to cardiolipids. In the mitochondria it will affect the electron transport chain, which makes the electrons unavailable for complex 1 thereby affecting ATP generation
What characterize the nervous system?
- CNS is protected by the BBB
- Highly specialized cells
- High degree of plasticity
- Limited (Slow) cellular regeneration
- Toxicity can affect cells at all levels
What are the targets for toxicity in the nervous System (NS)?
1) Neurotransmitter concentration
e.g. of drug Isoniazid
2) Receptor function
e.g. of drug Curare
3) Intracellular signal transduction
e.g. of drug Botulinum toxin
4) Signal terminating process
e.g. of drug Organophosphorous compounds
What characterize toxicants that induce neurotoxicity
They:
1) Possess certain physical characteristics
Does it pass Blood Brain Barriere? – Methyl Hg
2) Use of specific uptake mechanisms
Transporters linked to target organ – Pb, MPTP (parkinsons)
3) Have a specific metabolism
Creation of toxicants – Designer drug, cresyl phosphate, 6-hydroxydopamin
4) Attack membrane structures
Methyl Hg
What is the biochemical mechanism behind toxicity from methanol?
Methanol induced multi-organ toxicity through the toxic intermediate formic acid.
Metabolism and patofysiology:
1) alcohol dehydrogenase oxidizes methanol to HCHO.
2) Formaldehyde dehydrogenase catalyzes HCHO to HCOOH (formic acid)
3) Formic acid inhibits cytochrome oxidase –> circulus hyperxicus of non-ionized HCOOH causes CNS depression and hypotension.
Dose-response: blindness ≥ 10 ml; lethal ≥ 30 ml
Toxic effect: Optic nerve and CNS damage
How is methanol toxicity treated?
Treatment: Ethanol, bicarbonate, dialysis
What is the biochemical mechanism behind toxicity from ethylene glycol?
Is in anti-freeze formulations.
Induces multi-organ toxicity
- Lethal dose: 100 ml
Metabolism and patofysiology:
1) Alcohol dehydrogenase oxidizes ethylene glycol to oxalic acid and aldehydes
–> oxalic acid –> crystal formation in the brain
–> in the aldehyde formation –> cerebral edema (blurred vision, nausea, coma)
Toxic effect:
CNS – crystal deposits and edema
Kidney failure – due to oxalate deposits
What is the antidote for ethylene glycol?
Antidote: alcohol due to it competing for alcohol dehydrogenase
What are organophosphates used for and what are their target?
Organophosphates are insecticides.
Target: inhibition of cholinesterase
What is the toxic effect of organophosphates?
There are two types of toxic effects:
1) inhibition of cholinesterases –> Lead to an increase in ACh –> increased stimulation / hyperactvity
2) delayed neuropathy
Which compound can induce delayed neuropathy and what is the mechanism behind?
Some organophosphates can cause delayed neuropathy.
Mechanism:
Activation of a membrane protein (neuropathy target esterase), not cholinesterase –> disturbs axonal metabolism.
Effect:
Cause peripheral and CNS axonal and myelin degeneration –> leg paralyse
What is the target and toxic mechanism for botulinum toxin?
Target:
ACh-R
Mechanism:
Absorption of botulinum toxin through transcytosis from the gut –> passes lipid membranes via. receptors –> degraded by peptidase in synaptosomes –> metabolites bind irreversibly to muscle ACh-R –> relaxation (paralysis)
What are the critical target organs for lead and how is damage manifested??
- Nervous system (encephalopathy, peripheral neuropathy)
- Hematopoietic tissue (anemia due to inhibition of 1) heme synthesis 2) aminolevulinic dehydrogenase, 3) incorporation of Fe)
- Reproductive organs (damage to testis spermatogenesis and decreased testosterone levels)
- Kidney (reversible tubular damage –> aminoacid-, glucosuria)
- General cell toxicant (carcinogen) DNA synthesis –> hyperplasia
What are the biomarker for detection of lead?
Main biomarker: Erythrocytes
- Bone is the X-ray biomarker
- Urine is also a biomarker
How is lead toxicity treated?
With Ca-EDTA
What is toxicokinetics for lead?
Pb2+
1) Uptake (via Ca2+ carriers) orally or through the lungs
2) Distribution to erythrocytes
What is toxicokinetics for lead?
Pb2+
1) Uptake orally (via Ca2+ carriers) or through the lungs
2) Binding to erythrocytes and bones (storage)
3) Distribution to organs – CNS (via Ca2+ carriers) and kidneys
4) Excretion through bile and urine
Organo Pb compounds:
1) Uptake orally, through the lungs or skin
2) Distribution to CNS
What is the biochemical effect of lead?
Biochemical effects:
- Pb binds to -SH
- ROS formation (mitochondria, Ca2+ dependent xanthine oxidase, cyclooxygenase and NO)
- Inactivates antioxidant enzymes (superoxidismutase (SOD) and catalase)
- Transported via Ca2+ carriers
- Interferes with Ca2+ in enzymes (e.g. phosphokinase C (PKC) and cause increased Ca+2 release from mitochondria
- Effects on neurotransmitter systems (glutamate (ionotropic receptor), dopamine & serotonin)
What is isoniazid used for and what is the toxic effect?
Antituberculosis drug.
Toxic effect: Peripheral neuropathia and hepatoxicity
Mechanism:
Causes hydrazone formation with vitamin B6 (pyridoxal phosphate) and this adduct inhibits the enzyme pyridoxal phosphate kinase –> degeneration
The toxicity is dependent of the acetylator phenotype
Which types of mercury exist?
Hg0 – elemental
Hg+2 – inorganic
Methyl- Hg+ – organic
What are the target organs for the different mercury and what is the mechanism for toxixicty?
Hg0: CNS (Instruments, Cl2 production, light bulbs)
Hg2+: Kidneys (Limited extent to the CNS)
Methyl-Hg: CNS
Mechanisms: Formation of ROS and high [Ca+2]
What are the characteristics of 6-Hydroxydopamine?
Effect: Sympathetic denervation, Parkinson-like phenotype
Mechanism:
It is similar to noradrenalin and is therefore is taken up in the synapse where it causes destruction via paraquinone formation–> ROS in dopaminergic neurons.
It is CNS selective.
What are the characteristics of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydro- pyridine)?
Byproduct of synthesis of some illicit drugs
Effect:
Rapid-onset Parkinson-like symptoms due to the destruction of dopaminergic nerves in substantia nigra
Mechanism:
It diffuses into astrocytes and is oxidized. The metabolic transformation by MAO B makes it a positive ion available for the specific dopamine transporter allowing active uptake into
