topic 23 Flashcards
Why is the liver vulnerable to damage by toxins? What does toxin injury in the liver present like?
Biotransformation of xenobiotics &
endogenous substances
Subject to action of parent toxins and/or
their metabolites
Dose-related & idiosyncratic
Toxic injury not unique histologically or clinically
Same pathology as other hepatic diseases;
such as steatosis, necrosis, inflammation, fibrosis, cholestasis
What usually happens in CYP phase I reactions? What else can happen? What is one possible toxic results?
Phase I usually “deactivates” the substance
However, some metabolites retain the activity of the parent or are even more active in reacting with cellular molecules
“Reactive metabolites” = unstable; including
free radicals, electrophiles or nucleophiles
Responsible for much toxin-induced hepatic
damage
What should happen with reactive electrophillic metabolites? What happens if that doesnt work? What are two examples of drugs that form reactive metabolites?
Electron-loving metabolite immediately attracted
to a molecule able to donate or share electrons.
eg, glutathione, the detoxifying conjugate,
having its nucleophilic sulfur atom
Otherwise, S, N, O atoms in cellular macro-
molecules of proteins, DNA, RNA are targeted.
…..forming “adducts”
Cyt P450 generates such reactive metabolites
examples: acetaminophen & carbon tetrachloride
What can happen with reactive metabolites at membranes?
Reactive metabolites may also add to double bonds or abstract H+ atoms from fatty acids in lipid bilayer membrane
Creates 2º lipid radicals that react with oxygen, leave a peroxyl residue on the fatty acid, and regenerate a lipid radical
Chain reactions/ repetitive cycles of membrane-
damaging interaction occur in the membrane
What is the classice hepatic lobule arrangement? Where is the portal triad located? Where are most CYP450 enzymes located? Where are most nutrients located? Where does acetaminophen do its damage?
Landmarks: Put central vein in the center & draw 3
rings around it
centri-lobular zone (CL)
Midzonal (MZ)
Periportal area (PP)
The portal triad surrounds the outside of the periportal area. This is where most nutrients are located. The CL zone is where most enzymes are and where acetaminophen causes injury.
How common is toxin caused hepatocellular carcinoma? What are 2 agents that can cause it? What is the most common promoter? What can cause angiosarcoma of the liver?
Hepatocellular carcinoma is rarely linked to toxins
Ethanol, aflatoxin (Aspergillus on moldy legumes
and grains)
Most common promoter:
Viral infection (HBV)
Angiosarcoma of liver
Vinyl Chloride
What are some suspected synthetic human hepatocarcinogens? Naturally occuring?
Synthetic
Dimethyl nitrosamine
Diethyl nitrosamine
DDT
CCl4
Chloroform (CHCl3)
PCBs
Naturally occurring
Pyrrolizidine alkaloids
Comfrey tea
Safrole
Sassafras
Arsenic
Why is the kidney vulnerable to toxin damage? What are the results?
Renal tissues exposed to all exogenous
substances excreted in urine
Toxin-induced injury can mimic many
types of renal conditions
In a patient with kidney damage, consider
all the other possibilities, too
Don’t be hasty in blaming a toxin
What are some therapeutic agents that lead to renal toxicity?
Antimicrobials
Aminoglycosides , e.g. gentamycin
Antifungal amphotericin
Antineoplastics
e.g. Cisplatin
Iodinated radiocontrast agents
Analgesics
e.g. Phenacetin, acetaminophen, NSAIDs
What are some occ. and env. toxins that lead to renal toxicity?
Occ & Env chemicals
Metals
eg, Inorganic mercury, cadmium, lead
Hydrocarbon solvents
CCl4,toluene
Aniline dyes (precursor to indigo)
Aniline derivatives used to make APAP
Diquat (herbicide)
Ethylene glycol
What part of the kidney is most commonly damaged? Where do toluene, analgesics, and gold each cause damage?
Proximal tubule most commonly injured
Most Cytochrome P450
So, most subject to reactive metabolites
Toluene: distal renal tubule
Analgesics: interstitium
Gold: glomerulus
What is the most common presentation of kidney damage due to toxins? How serious is it?
Most common presentation of toxic injury: acute renal failure
Relatively abrupt decline in plasma
filtering and tubular processing
Grades of severity from minor impairment to total failure of both kidneys
Substantial degree of recovery from acute
injury often possible
What is the most common cause of acute renal impairment? How does it work? What are 4 toxins that can cause it?
Acute tubular necrosis ATN most common cause
of acute renal impairment
Tubule cells damaged, swell, die & collapse into
the lumen
- CCl4
- Gentamycin
- Mercury
- Acetaminophen overdose
Where is orellanine found? What renal condition does it cause? What is the pathology? How does it happeN?
Direct toxin-induced acute renal injury:
Tubulo-interstitial nephritis
Orellanine in Cortinarius mushrooms
Interrupts ATP production
Pathology: Unremarkable glomeruli; interstitial
inflammation
What are 3 things that can cause tubule lumen obstruction?
Obstruction of tubule lumen
Oxalate crystals
• Ethylene glycol metabolism
Myoglobin from muscle breakdown
• 2,4-D; neuroleptic malignant syndrome; any
toxin causing prolonged seizures
Hemoglobin from intravascular hemolysis
• Arsine gas, chlorates
What are 3 agents that can cause chronic renal impairment through chronic exposure?
Slowly progressing decline in renal function
Tends to be permanent
Associated with chronic exposure, eg,
Phenacetin (cumulative 2-kg exposure)
Cadmium
Toluene (eg, glue sniffing) causing distal
renal tubular acidosis
What are some agents that are risk factors for urinary tract cancer?
- Cigarette smoking
- Poly Aromatic Hydrocarbons (PAH)
- Asbestos
- Phenacetin
- Cadmium
• Aristolochia fangchi (herb used for weight loss)
BOARD EXAM ALERT
What does reproductive toxicology include?
Study of disturbances induced by chemicals throughout the entire reproductive cycle
- Impairment of reproductive functions in parents
- Effects on the progeny:
• “Developmental” toxicology specifically studies effects prior to adulthood, only some of which are “birth defects”
What are structural developmental defects known as? How are they caused? What percent of live births have them? What percent of those are due to drugs or toxins?
“Terata”
Regarded as the classic ‘birth defect’
• Malformation evident at birth
• Short period of embryonic vulnerability
Causative agents are “teratogens” and produce specific abnormalities at specific times during gestation
Dose-related incidence
Only ~ 2% of live births show terata; most
of which are minor
~ 5% of these (1 in 1000) are due to drug or toxin exposure
What is the number one principle of reproductive toxicology?
Expression of toxic effect depends on when
in fetal development exposure occurs
Critical period for terata is organogenesis (wks 2 thru 8)
To cause structural damage, exposure to a
potential teratogen must occur DURING - not before or after - the critical period in organogenesis when
that particular body part is arising
How does generalized toxic effect manifest? What happens if mother is sick?
If mother is sick for any reason, or is affected by toxin, it may also affect the embryo or fetus
“Indirect effect” of mother’s illness on baby
Generalized toxic effect manifests as general growth retardation
“Low birth-weight baby”
eg, smoking, ethanol
How and when might medicine that a mother is taking affect the fetus?
In 3rd trimester … pharmacologic or toxic activity in fetus
Sufficiently matured … many target organs
respond to the agent
May be serious, often reversible: eg
Hypotension /ACE inhibitor Hypoglycemia/ sulfonylurea
Withdrawal from maternal use of abusable
drugs – narcotics, benzodiazepines, cocaine, amphetamines, etc
What are some agents that affect fertility in men?
Many suspects but few proven guilty, eg
alcohol …testicular toxin
Agents associated with low semen quality
- Lead, mercury
- 2,4-D (dichloro phenoxy acetic acid)
- Ethylene glycol ethers
- Estrogens (environmental estrogens?)
- Di Bromo Chloro Propane (DBCP)*****
BOARD EXAM ALERT
What are some agents associated with difficulty in conceiving for women?
Difficulty conceiving associated with
- Volatile organic solvents
- PCBs
- Pesticides / agricultural work
- Formaldehyde
What is the risk equation? What is a definition of risk? what is a definition of hazard? What is a definition of hazard?
RISK =HAZARD x EXPOSURE
Key concept: Risk is a function of both the hazard of the material and the extent of exposure to the material
Risk: the chance that a given adverse effect will occur due to a given exposure. Risk is scenario-specific
Hazard: the total spectrum of harmful potential inherent to the chemical, and the conditions under
which the adverse effects occur
Exposure: description of the conditions of contact of the individual with the substance
• How much (quantity, dose, concentration)
• How long (duration)
• How often (frequency)
To change risk, change the exposure
What are dose response curves used to determine in toxicology? What are two landmarks to find on a dose response curve? Why look for those landmarks?
Note: To determine the dose that does NOT ‘make the poison’
NOEL (No-Observable-Effect Level) An actual test dose that did not produce the observable effect in the test
population LOEL (Lowest-observable-effect level) The lowest actual test dose that *did* produce the observable effect
Just as larger doses affect more of the population, lower doses affect fewer of the population
Once the dose is low enough, it will fail to adversely affect ANY individual
It is clinically important to have some idea of the dose that is insufficient to cause a harmful effect
What is the threshhold dose? How is it estimated?
Extrapolated dose below which the effect cannot be detected in the tested population & above which the effect first becomes apparent
Between the highest NOEL & the lowest LOEL value
Closest approximation is just a smidgen above the
NOEL.
What happens once a LOEL and NOEL are found in animals?
NOEL and/or LOEL obtained from animal
experiments
“Safety factors” aka “uncertainty factors” are applied to account for inter-species and inter-individual differences
“Safe” exposure level is determined
Forms the basis for regulation of an allowable
chemical residue in food, water, air, or soil.
LOWER by orders of magnitude than the dose
that did not affect test animals
Why is LD50 useful?
VERY IMPORTANT: Basis for comparison
of potency of chemicals
Allow relative ranking with respect to ability to kill the test animal species
Don’t necessarily need to compare the dose response curves
Just compare the midpoints (LD50)
