Professional Documents
Culture Documents
Biological System
K2
Elimination
Toxicokinetics
1. 2. 3. 4. 5. Uptake Transport Metabolism & Transformation Sequestration Excretion
Uptake routes
1. Ingestion (toxicity may be modified by enzymes, pH and microbes) 2. Respiration (Air borne toxicants) 3. Body surface (Lipid soluble toxicants such as carbon terta chloride and organophosphate)
Uptake Barriers
1. Cell membrane
2. Cell wall/cuticles/stomata
Uptake of Toxicants
1. 2. 3. 4.
compound Co = Concentration of the toxicant outside the membrane Ci = Concentration of the toxicant inside the membrane X= Thickness of the membrane
Uptake by Pinocytosis
For large molecules ( ca 1 um) Outside: Infolding of cell membrane Inside: release of molecules Example:
Airborne toxicants across alveoli cells
Deposition
Toxicant Pb Cd OC, PCB OP Aflatoxin Target organs Bone, teeth, brain Kidney, bone, gonad Adipose tissue,milk Nervous tissue Liver
soluble form (more polar & hydrophilic) 2. Dissolve in aqueous/gas phases and eliminate by excretion (urine/sweat) of exhalation 3. Sequestrate in inactive tissues (e.g bone, fat)
P450 system
A heme-containing cytochrome protein located in ER, and is involved in electron transport. Highly conservative, occur in most plants & animals Two phases of transformation May increase or decrease toxicity of toxicants after transformation (e.g turn Benzo[a]pyrene into benzo[a]pyrene diol epoxide, and nitroamines into methyl radicals) Inducible by toxicants
Induction of P450
Toxicant Aryl Hydrocarbon Receptor
Toxicant-Receptor Complex
hours
Phase I Transformation
Mixed Function Oxidase (MFO) System in smooth ER is responsible (Microsomes) In vertebrates, primarily found in liver parenchyma cells, but also other tissues (e.g intestine, gill) In invertebrates, found in hepatopancrease & digestive glands Lower MFO activities in molluscs Add polar group(s) to increase hydrophilicity for Phase II transformation
Hydroxylation
NADP NADP+
Phase II transformation
Cytochrome P450 II enzyme systems in cytosol is responsible Covalent conjugation to water soluble endogenous metabloites (e.g. sugars, peptides, glucuronic acid, glutathione, phosphates & sulphate) May involve deamination, acyclic hydroxylation, aromatic hydroxylation, and dealkylation Further increase hydrophilicity for excretion in bile, urine and sweat
Dehalogenation:
R-Cl ---------------------------------> R-H + Cl+
Glutathione-S-transferase (GST)
O GST R------R ----------------------> HO-R-SG
GST
Sequestration
Animals may store toxicants in inert tissues (e.g. bone, fat, hair, nail) to reduce toxicity Plants may store toxicants in bark, leaves, vacuoles for shedding later on Lipophilic toxicants (e.g. DDT, PCBs) may be stored in milk at high conc and pass to the young Metallothionein (MT) or phytochelatin may be used to bind metals
Excretion
Gas (e.g. ammonia) and volatile (e.g. alcohol) toxicants may be excreted from the gill or lung by simple diffusion Water soluble toxicants (molecular wt. < 70,000) may be excreted through the kidney by active or passive transport Conjugates with high molecular wt. (>300) may be excreted into bile through active transport Lipid soluble and non-ionised toxicants may be reabsorbed (systematic toxicity)
Tutorial Questions
1. Find TWO enzymes/proteins which are inducible by xenobiotics or metals 2. Molluscs have low P450 activities. They are often used as pollution indicators for metals and xenobiotics. Explain why. 3. Lipophilic compounds may normally have a longer biological half life. Explain why. 4. Why exposure of animals to sub-lethal level of toxicants may increase tolerance of the organisms to the chemical.