Principles lec 5 2013

ultimately depends on concentration and position of

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Unformatted text preview: bile (next class, but remember this!). Ultimately depends on concentration and position of specialized transporters **Biliary excretion can be increased by agents that induce enzymes and transporters** rough benchmark for size this is not only a product of size, but there are specific transporters in higher abundance on the bile side can up regulate proteins if needed Liver Secretion (Transporters) Different transporters expressed on different sides of the cells Location will play a role in determining excretion pathway Abundance can be increased and decreased (dynamic system) Eg. Xenobiotics bind to receptors that instigate protein synthesis if high concentrations are encountered (more on this Monday) Enterohepatic Circulation A. Liver if a big fat sol chem, you go to liver and get uptaken by hepatocytes, hepatocytes change you so you’re not as fat soluble, then you go to bill ducts to gall bladder, then when you have a large fatty meal bile is excreted and all this goes to the small intestines • Portal blood flow (from bowl) high exposure • Active uptake Large MW compounds - active secretion into bile • Metabolism conjugation Bile B. Gut bacteria in gut can act on changed molecules and make them lipid sol and they can be re uptaken then you go back to liver and process is repeated in the end you do not get eliminated and residency time is increased Lipid soluble chemicals reabsorbed into portal blood OR Bacteria remove conjugate & release lipid soluble chemical which is then reabsorbed into the portal blood Enterohepatic Circulation Blue T = more water soluble (May or may not be charged) **Dimethyl mercury** happens with chloronated biphenol molecules or Hg compounds T CONJUGATION o T o T +- T T +- T o Biliary excretion o T T o T +- o T +- T +- Fecal add slide above this Glandular Secretions diffusion mediated process Mammary Diffusion mediated, pH is slightly acidic: Therefore BASIC toxicants can get trapped (protonated conjugate acid) Also 3-4% fat content, get some lipophilic concentration get higher concentration of xenobiotics in milk that get PAH, DDT excreted through milk Significant for accumulation in children Sweat and Salivary Glands need to be fat soluble or very small water soluble compound Diffusion mediated (no transporters) need fat soluble forms to cross membrane Electrolytes, urea, small water soluble molecules (ethanol). Example of Stable Lipophilic Chemical Toxicokinetics: DDT Lactating Mother Oral intake 0.0005 mg/kg/day DDT Mother’s Body Fat 1.0 ppm DDT Milk (eggs) contains 0.08 ppm DDT Infant Dosage 0.0112 mg/kg/day “Infant Dose 20X greater than mother” Also PCB and methylmercury (will undergo enterohepatic circulation) **For next class! How does the body eliminate lipid soluble chemicals?...
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