Environmental Chemistry
Terms
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- Adsorption
- impacting molecules are attached to the surface
- Mobile sources of pollution
- EPA: Cause more 1/2 of 2 major causes of smog: VOCs: Volatile organic compounds NOx: Nitrogen oxides ~90% of CO and more than 1/2 of all hazardous air pollutants
- Air pollutants
- -CO (Carbon Monoxide) -SO2 (Sulfur dioxide) -NOx (Nitrogen oxides) -VOCs (volatile organic compounds) -PM (suspended particles)
- Temperature Inversion
- Warm air over cool air layer (close to the surface of the earth). During temperature inversion, pollutants can build up when they are trapped close to the earth's surface
- Non-Gaseous components of troposphere
- -Particulates >10um, solid or liquid -Aerosols: <10um solid or liquid
- Absorption
- impacting molecules are drawn an dissolved in liquids or aerosols
- Phase II reaction
- occur in cytosol. Polar products may be excreted directly or, in the case of eukaryotes, made more excretable by conjugation with highly polar endogenous conjugates… less lipophilic, more water soluble, less toxic and more easily eliminated. Functional groups added during phase I serve as “chemical handles†for reaction with Phase II conjugates.
- Phase II
- xenobiotic compound, often Phase I product. Xenobiotic from Phase I + conjugating agent--> conjugating product (higher polarity, greater water solubility, more easily eliminated)
- Glucuronide Conjugation
- Phase II reaction that occurs in microsomes (ER). Exception to Phase II reactions which occur in cytosol. Rapidly formed. UDPGA + HX-R --> conjugate of xenobiotic with glucorinide. Reaction occurs with activity of glucuronyl transferase enzymes which co-occur in ER
- Lamprey toxin
- species-specific phase II capability. UDPGA=Uridine diphosphate glucuronic acid TFM (4-nitro-3-trifluoromethylphenol) + UDPGA (uridine diphosphate glucuronic acid) --> TFM-glucoranide Lampreys are not able to do this reaction, they do not have glucuronyl transferase. Used to control lamprey populations (to bring up pops of lake trout)
- Phase II: Glutathione conjugation
- Major pathway of xenobiotic metabolism. Glutathione is a small tripeptide of glutamic acid, cysteine, and glycine. The SH group reacts with a phase I metabolite, typically in the liver. This conjugate may be lost by bile excretion, or the glutamate and glycine may be lost and the remaining cysteine-only conjugate can further react with an acetic acid to form mercapturic acid, a common metabolite that is readily excreted. Glutathione transferase is a common enzyme found in all tissues of the body
- Sulfate conjugation via PAPS: ROHs and Aryl Amines
- PAPS=3'-phosphoadenosine-5'-phosphosulfate Energetically expensive, but highly effective. Complex is ionized at physiological pH
- Acetylation
- Acetyl transferase Addition of -CO-CH3
- 4 general categories of toxicity mechanisms
- 1) disruption/destruction of cellular structures (usually membranes), solvents, free radicals. 2. Direct chemical combination with a cellular constituent (CO & hemoglobin, heavy metals, and -SH groups, DNA adducts) 3. Influence on enzyme or receptor function 4. Initiation of a secondary action (allergic reaction, CCl4 induced release of norepinephrine induces liver damage, Ah receptor and MFO induction) - Ah= aryl hydrocarbon receptor. Famous for having agonists that include DDT, dioxin, PBC's, etc. - Turns on P-450 enzymes producing deleterious reactions. Pathophysiological classification
- Major Mechanisms of Toxicity: Non-Specific Narcosis
- - Does not relate to making or breaking bonds, reacting with receptors, etc -Effects also non-specific: metabolic or/and sensory depression -Examples: ether, chloroform, light alkenes, many industrial solvents -Broadly related to Kow -Tissue specific concentrations comparable across a broad range of species *Causes physical effects with membranes--> interact with hydrophobic sides of proteins, slowing down the metabolic reactions. Affect mainly the Central Nervous System
- Major Mechanisms of Toxicity: Generalized effects -Inhibition of oxidative phosphorylation
- Halo and nitrophenols (such as pentachlorophenol) - Affect the electron transport chain in the mitochondria: Phenols are lipophilic... so they penetrate the membrane. Phenols are sufficiently acidic (proton donors) to disrupt restriction to proton flow Effects-->proton gradient in mitochondria is affected. Chemiosomotic pressure within mitochondria is lost and ATP production is decreased/stopped
- Major Mechanisms of Toxicity: Arsenic
- Interferes with Glycolysis: Pyruvate is not formed, so Krebs cycle is stopped -Sodium Arsenite (ant bait), calcium arsenate (molluscicide), lead arsenate (insecticide) -Trivalent arsenic bond angles just right to form a disulfide bridge with SH-groups on key enzyme (dihydrolipyl transacetylase) in metabolism of pyruvate during glycolysis
- Major mechanisms of toxicity: Liver/hepatopancrease
- -Major site of xenobiotic activity -high risk of hepatotoxicity -Lipid accumulation -Necrosis -Lipid peroxidation -Ah receptor-related toxicity
- Mechanisms of toxicity: Disruption of cytoprotective response: COX inhibitors
- COX Inhibitors: -Prostaglandins: eicosanoids derived from arachidonic acid (mediators of inflammatory processes) -produced by 2 major forms for cyclooxygenase: COX-1 and COX-2 -Also play important role in mucosal defense, cytoprotective activity in liver -if inhibited, results in increase susceptibility to liver toxicity COX-1: Forms eicosinoids fro cytoprotective inflammation COX-2: Inducible enzyme that is turned on when inflammation occurs
- Biological Basis for Organ-Selective Toxicity
- -Tissue-specific toxicokinetic factors -Organ-selective uptake, distribution, accumulation (non-specific transporters or molecular homology) -Tissue specific toxicodynamic factors -Tissue-specific expression of receptors -Tissue-specific binding of xenobiotics to macromolecules -Tissue-specific deficiencies in pathways to detoxification repair
- Molecular Homology
- -Toxicant mimics physicochemical properties of endogenous compound. -Toxicant follows pathways intended for endogenous metabolite Example: Inorganic mercury causes nephrotoxicity, while organic Hg-methyl-Hg results in neurotoxicity (Tissue-selective uptake of Hg)
- Mercury poisoning: Molecular homology: Toxicant form influences MOA
- Hg toxicity due to covalent binding with thiol groups of critical aa's (affect protein function). Organs with high []