3 tox response of lung and kidney Flashcards
what do we need to recall in the case of the kidney as a target organ?
-urine is a major excretion route for most xenobiotics
-highly perfused organ
-concentrates xenobiotics in filtrate
-transports xenobiotics across tubular cells
-has moderate expression of biotransformation enzymes
what are the major functions and form of the kidney?
major functions: MEARBE
-excretion of metabolic (nitrogenous) wastes
-regulation of extracellular fluid volume
-electrolyte homeostasis
-acid-base balance
-blood pressure regulation
-metabolizes vitamin D to active form
what are nephrotoxicants examples (kidney toxicants)?
-certain heavy metals, halogenated hydrocarbons (forever chemicals, PCBs, DDT, DDE) and drugs (especially antibiotics and analgesics) are the major examples
which cells in the kidneys are the most susceptible to nephrotoxicants?
-proximal convoluted tubule (PCT) (in nephron) cells are the most susceptible, due to:
1. tubular transport of many xenobiotics occurs in PCT cells; can result in accumulation in cells
2. greatest CYP enzyme activity among kidney cells (bioactivation potential)
3. high metabolic activity (lots of mitochondria) (more susceptible to oxidative stress)
-glomerular cells also susceptible (can affect ability to filter blood)
what are the ways we can test kidney function?
-urinalysis
-blood analysis
what is urinalysis?
i. proteinuria:
-increased levels of small proteins indicate loss of PCT reabsorption, indicating toxicity to PCT cells
-increased levels of large proteins indicates effects on glomerular cells
ii. glycosuria: increased glucose in urine indicates tubular dysfunction (in absence of hyperglycemia, which is a very reliable marker of diabetes)
iii. functional enzyme tests: e.g. GGT in urine (when cells are dying by necrosis, GGT shows up)
what is blood analysis?
i. blood urea nitrogen (BUN): increased urea (major nitrogenous waste product, gets rid of excess nitrogen) in blood indicates reduced glomerular filtration rate (GFR)
ii. creatinine clearance: presence of creatinine in blood indicates impaired kidney function
what are the sources of lung damage?
- oxidative stress (e.g. ozone, NOx (nitrogen oxides), smoke)
- gases and vapors (e.g. chlorine(Cl2=mustard gas, combines with water to form HCl), ammonia, volatile solvents)
- particles and aerosols
-size is important (the smaller the particulate, the more toxic it is because the deeper it gets)
-PM2.5 (particulate matter <2.5 nanometer) is associated with human respiratory toxicity, including death
-also nanoparticles (<0.1 nanometer)
what are the 3 regions of the respiratory system?
-nasal passages
-conducting airways (trachea and bronchi)
-gas exchange region (alveoli)
what is particulate deposition?
emphasizes how important size is
-nose hairs and abrupt turn are first filtration site
-the smaller the particulate the more it travels in the lungs
what are the acute effects of the respiratory system?
-can be reversible or irreversible
-can directly affect respiratory tract, be absorbed systemically to cause effects in other organs, or both
1. airway reactivity
2. pulmonary edema
what is airway reactivity?
-bronchial smooth muscle is target cell type, usually effect is muscle contraction
-major concern: asthma and air pollution (gases and fine particles), especially in urban areas
what is pulmonary edema?
-fluid accumulation in lung, reduces O2/CO2 exchange
-e.g. Cl2, NH3 gas
what are the chronic effects of the respiratory tract?
-usually irreversible effects
1. fibrosis
2. emphysema
3. asthma
4. neoplasia
what is fibrosis?
-increased extracellular matrix protein (e.g. collagen) production by fibroblasts, builds up in alveoli
-lungs get smaller and stiffer
