Term
| What are gap junctions and what are their functions? |
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Definition
| Gap Junctions are channels between cells. 'An intercellular network of protein channels that facilitates cell-to-cell passage of ions, hormones, and NTs.' connexin-transmembrane has 2 extracellular loops (docking sites), which form rosette of subunits called connexons. 2 adjacent connexons=gap junction. Functions: Exchange of cellular signals (ex. cAMP, Ca2+, MAPK), Conduction of electrical impulses (ex. depolarization of nerve cells in brain, & heart msl contraction-Na+ migrate thru gap junctions-wave of contraction.) |
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Term
| How are gap junctions regulated in normal cells? |
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Definition
| Kinases, Oxyradicals (GSH, MAPK), Second messengers (Ceramide, cAMP, Ca), Electrical signals (ion currents); phosphorylation-gene expression/breakdown, ions Na+, Ca2+-cause closing, MAPK, Ca2+-signaling, cAMP |
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Term
| Describe four ways that xenobiotics could affect gap junctional signaling. |
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Definition
| Inhibit connexin gene expression or protein synthesis (pesticides-organochlorin-> lindane, still found in the environment), Blocking channel (PAHs, DDT, Dioxins), Abberant phosphorylation (some pesticides, heavy metals, arsenic), Abberant localization (not transported to lateral sides of epithelial cells) |
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Term
| Consequences of interruption of Gap Junction Intercellular Communication (GJIC) |
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Definition
| cancer, teratogenesis, reproductive dysfunction, neurologic disorders Cardiovascular dysfunction/cardiotoxicity, Endocrine dysfunction, Alter apoptosis &adaptive responses |
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Term
| Pharmacological implications of GJIC |
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Definition
| under development, arrhythmia (atrium & ventricle contractions not in sync),atherosclerosis (mice w/a incr cholestrol diet show decr in connexin expression; statin incr connexon expression), cancer (stimulate GJIC), epilepsy |
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Term
| Describe the ras-MAP (mitogen activated protein) kinase signaling pathway. |
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Definition
| Ras activation: Activated by GTPase not a G-ptn; associated with membrane receptor-activation of Ras via GEF ptn. This leads to the Phosphorylase casacade starting with MAPKKK. About MAPK: Ras phosphorylated->MAPKKK, MAPKKK phosphorylated->MAPKK, MAPKK phosphorylated->MAPK; often but not exclusively associated w/Ras; MAPK usually activate transcription factor, MAPK may also activate enzymes or affect cytoskeleton (shape, mov't, vesicular traffic); Ex. of signaling intermediates: AP-1 transcription factor-> Dimer fos, jun; hetero-fos/jun; homo-fos/fos, jun/jun; Cellular Responses to Stress: UV, ionizing radiation, chemicals, growth & differentiation of cells (C.S. 19) |
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Term
| Discuss the functional relevance of AP-1 (activator protein 1), ERK (Extracellular Response Kinase), jun/fos, p38 |
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Definition
| AP-1: transcription factor, Dimer fos, jun; hetero-fos/jun; homo-fos/fos, jun/jun-> cellular response to stress, UV, ionizing radiation, chemicals, growth & differentiation of cells; ERK: ERK-1->cell division, growth, jun/fos:Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK)->activate AP-1, often involved in stress response or cell death (apoptosis); p38->also involved in stress response, cell death |
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Term
| How do toxicants affect MAPK pathways? |
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Definition
| Toxicological Relevance: very frequently involved in responses to xenobiotics; ex:) heavy metals & arsenic, activate MAPK and ras=> overproliferation->cell death (apoptosis), PAHs also stimulate Ras |
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Term
| What are the metabotropic post-synaptic receptors? How do they function? Give 3 examples with pharmacological significance. |
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Definition
| Def: A receptor whose ion channels are opened indirectly by a second messenger. Function: they typically activate a G-ptn (activates Adenosyl Cyclase) sometimes activate PKC (gene or enzyme activation->channel opening) or MAPK. They are slower acting and longer lasting than ionotropic-> thought memory, emotions; ex:) serotonin, catacolamines, GABAB, mGlu muscarinic ACh (muscarine); Pharm sig: Opiate receptors- natual function bind to endorphins (NT that dull pain), also bind morphine and heroin; Cannaboid receptors- bind to endocannaboids (ECs), also to tetrahydrocannibinol(THC) (active ingredient in cannibis)->stimulate appetite and fat synthesis, EC antagonists dev as diet pills, THC stimulate appetite & decr nausea in chemotherapy & AIDS pts.; Adenosine receptor-caffiene, stimulatory receptor |
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Term
| What are andrenergic receptors? Where are they located? What is their function? What is the pharmacological significance? |
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Definition
| Def: receptors that bind to adrenalin and norepinephrine and release hormones and NTs (coupled G-ptn receptors that are targets of catacholamines)->3 main types- alpha1, alpha2, & beta; Location: nerves, sm msls, carbohydrate/fat metabolizing organs, liver, and adipose tissue; Function-stimulate sympathetic nervous system-action incr breathing, incr HR, incr BP, decr digestion; Pham sig: beta blockers used to treat high BP-> decr heart beat strength, treat angina |
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Term
| What are cytokines? What are 4 characteristics of cytokines? |
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Definition
| Def: extracellular signaling mcls->ptns, peptides; Char: Transient expression, Autocrine or paracrine functions, Not synthesized by gland, Exert functions via cell surface receptor |
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Term
| Give examples of signaling pathways in 4 cytokines. |
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Definition
| TNFalpha: form trimers and bind to alpha trimeric receptor, activation of NFKB->cell protection-stress ptns antioxidant enzyme, cell death (apoptosis); inhibited by inhibitor (IKB), TNFa, IL receptor->kinase cascade, phosphorylates IKB, releases NRKB; TGFB: a SMAD pathway, ligand binding->self phosphorylation of smad(2,3) dimerizes w/ex:)smad4->cause gene expression; Interfons: JAK-STAT (Janus Kinases-signal transduction & transcription) pathways, ligand binding->phosphorylation of JAKs (previously bound to the receptor)->STAT binding and phosphorylation, separate and cause transcription; Chemokines: variety of pathways, G-ptn pathways or JAK-STAT |
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Term
| How are cytokines involved in toxicology? |
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Definition
| 1)TNFa-b) Xenobiotic-induced inflammation->damage to tissues=release of TNFa as well as inflammation;a) Activation of MAPK-> ex:) PAHs, DDT stimulate MAPK, which then incr TNFa expression & inflammation; 2)Chemokines-induced by chemical-incudced tissue damage, which leads to attraction of WBCs & tissue damage; 3)TGFB-induced chemicals, ex:)heavy metals have cell proliferation ex:) lung fibrosis->fibroblasts->scarring; Pham implications: TNFa-chemotherapy cause cancer cells to die, control inflammation by binding to cytokine receptors; interferon therapy-antiviral treatments & chemotherapy |
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Term
| How are Eiconosoids synthesized? What is their mechanism of action? What types of pharmacological agents can be used to regulate Eiconosoid synthesis or receptors, & for what function? |
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Definition
| Synthesis: Fatty acid derived- Formation from arachadonic acid (AA): phospholipids react w/phospholipase A (PLA) to form AA, which leads to the synthesis of leukotrenes, thromboxanes, & prostiglandins. Prostiglandins are formed via cyclooxygenases (COX1 & COX2) COX1-constitutive, COX2-induced; Other signaling pathways for AA: 2nd messenger, activate PKC,MAPK, cAMP pathways; MOA: Prostiglandins-stimulate inflammation, sensitize pain centers of the brain, chemoattractants for WBCs; Leukotrenes-stimulate inflammation and induce bronchoconstriction; Pharm agents: 1)COX inhibitors-COX2 inhibitors-NSAIDs, ex:)naproxen, asprin, ibprofen; these suppress prostigladin (pain, swell) synthesis, Also prostiglandins (& thromboxanes) cause platet aggregation=preventative for heart attacks, COX3-brain, fever (maybe), headaches; not involved in inflammation, inhibited by NSAIDs, acetaminophen; 2) Leukotrene inhibitors-ex:) allergy medicines->Allegra; 3)AA & Alzheimer's- ex:) mice overdosed w/AA, therefore developed Alzheimer's disease-like symptoms, AA used for memory-but also->endocanniboides (link b/n marijuana use & memory loss), overstimulation of cannaboid receptor...? |
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Term
| Describe the types of leuktrenes involved in innate and aquired immunity. |
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Definition
| 1)Innate immunity- no previous exposure to pathogens required, function 1st time they are exposed, Macrophages: amoeboid cells, engulf pathogens, present antigens to T-cells, any tissue, R resident in skin, lungs, GI; NK cells: kill virus-infected or cancer cells, kill anything w/out 'self antigens' releases chemicals called perforins and proteases; Granulocytes: (neutrophils, basophils, eosinophils), phagocytize pathogens, release protelytic enzymes, respiratory burst->produce certain oxygen based free radicals ex:) superoxide-O2* also produce H2O2 & HClO (bleach) Dendritic cells: found in skin, carry Ag (forgein ptn) to lymph node, then present it to T cells Monocytes: in circulation can enter tissue; Aquired Immunity-previous exposure, 1st exposure-how to make an Ab (Immunoglobin)-bind to Ag, agglomerate viruses, mark cells for destruction, B lymphocytes: made and mature in bone marrow, exposure: B cell->plasma cell (makes Abs) or memory cell; T-lymphocytes: formed in bone marrow, mature in thymus; Tcell->cytotoxic Tcell (kills anything w/forgein Ag or bound to Ab, release perforins & proteolytic enzymes, induce cell death by binding to death receptors or target cell); Helper cells (effector helper cells-release stimulatory cytokines, memory T, regulator-secrete TCFbeta & other cytokines stop immune process |
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Term
| Describe 3 general ways toxicants can affect the immune system. |
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Definition
| Types of immunotoxicity: Immunosuppression, Leukocyte mediated toxicity, Immunoenhancement |
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Term
| Discuss examples of macrophages, Kupffer cell, & neutrophil-mediated immunity |
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Definition
| Types of Leukocyte-mediated to toxicity: 1)Macrophage-mediated-ex:) exposure to gaseous metals or particulate (e.g. shoot); stimulation of aveolar macrophages, respiratory burst release H2O2, O2*,HClO, release cytokines->inflammantion & fibrosis; 2)Kupffer cell-mediated: Liver resident macrophages, upto 15%of liver!, liver damage ex:) acetaminophen & CCl4; leads to KC activation which incr cytokines-inflammation attract other WBC & release O2*; H2O2, HClO; 3) Neutrophil-mediated: attracted by cytokines from KC, cause incr cell adhesion mcls (ICAM), infiltrate live tissue and produce O2*; H2O2, HClO and proteases inside liver..(this leads to death) |
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Term
| What is the role of inflammation in producing and enhancing toxic effects of chemicals? What role do lipopolysaccarides (LPS) and COX2 inhibitors play in suseptibility to toxicants? |
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Definition
| Inflammation, LPS, & susceptibility to toxicants: bacterio-endotoxins (LPS), mice dosed w/LPS->inflammation, which lead to incr susceptilbility to chlorinated aromatic hydrocarbons, exposure to xenobiotics->release of LPS from microflora in gut. Multiple Effects: incr LPS leads to inflammation, which leads to incr susceptibility, which can lead back to inflammation. Xenobiotics can also lead to tissue damage, which leads back to inflammation or xenobiotics can lead to back to LPS, which also leads back to inflammation. (cycle!) re:) COX2 leads to inflammation |
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Term
| Describe 3 mechanisms whereby toxicants can cause immunosupression. Give 4 examples of immunosupporessive toxicants. |
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Definition
| Mechanisms: effects on thymus, effects on immunopoetic tissue, effects on mature leukocytes; Examples: DDT, PAHs, Pd, Cd, Hg, pesticides, PCBs, dioxins. |
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Term
| Give 2 examples of how pharmacological drugs can be used for immunosupression. |
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Definition
| 1)Chemotherapy: unintended immunosuppression kill rapidly dividing cells WBC & stem cell rapidly divide; 2) Immune-suppressing drugs: inhibit cell division & organ transplants, ex:) colchicine |
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Term
| Describe autoimmunity, and how drugs or toxicants can cause autoimmune reactions. |
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Definition
| autoimmunity is a reaction against native ptn or 'you make Ab against your own ptns'; Chemical-induced autoimmunity: bc of haptenation (when chemicals bind to ptns covalently or stable complexes), 'mess up' selection of Tcells in thymus->result in autoreactive Tcells; Immunoallergy: Biology of allergy: Sensitization reaction-make Abs to Ag then dendritic cells bring Ags to lymph nodes where memory Tcells & Abs attached to mast cellls are. Elicitation-immediate->mast cells, release histamine and other inflammatory cytokines, inflammation bronchoconstriction & irritation of mucuous membranes |
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Term
| Describe the types of Histamine receptors & their functions. Discuss drugs that can be used to block histamine receptors, & their indications. What role does histamine play in the allergic reaction? |
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Definition
| Histamine receptors & pharmacology: H1-inflammation & allergy, act as NT, histamine blockers bind to H1; H2-produced by stomach epithelia, stimulates acid production, acid controllers bind to H2 receptor, (some antacids); H3-neurotransmission, primary found in post-synaptic cells |
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Term
| Discuss the molecular mechanisms behind Type I (Immediate), Type II (Ab-dependent cytotoxic), Type III (Immune complex-mediated), and Type IV (Cell-mediated or delayed) hypersensitivity reactions. |
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Definition
| Type I: 1)Penicillin G metabolized to penicilloic acid reacts w/lysine of ptn to form hapten-ptn complex. 2) Complex cross-links 2 IgE immunoglobulins bound to mast cell by Fc receptors. 3) Mast cell degranulates and releases performed mediators of inflammation & lung hyperreactivity 4) Leukotrienes & thromboxanes are synthesized 5)Cytokines typical of Th2 cells are released TypeII: Complement-Independent Cytotoxic Lysis-1)Forgein Ag attaches to surface of normal cell (i.e. RBC, platet, etc.) 2) Ab (IgG) is directed against foreign Ag. 3) Cytotoxic cell attaches to Fc portion of Ig, stimulating release of cytotoxic granules. Innocent bystander cell to which Ag is attached is lysed. Complement-Dependent Lysis- 1)Forgein Ag attaches to surface of normal cell (i.e., RBC, platet, etc.) 2)Ab (IgG) is directed against foreign Ag. Complement fixes to complement receptors on target cell membrane, inducing lysis. Type III: 1)IgG or IgM produced against soluble Ag, & Ag-Ab complexes are deposited in tissues. 2)Platets interact w/immune complexes leading to aggregation & microthrombi formation. 3)Complement is activated leading to release of vasoactive amines & chemotactic factors. 4) Chemotactic factors attract inflammatory cells to site. 5) Local tissues damaged by lysosomal enzymes released by phagocytes. Type IV: Induction of Sensitization- 1) Hapten penetrates the epidermis & forms a complex w/a ptn carrier. 2) The hapten-carrier complex is processed by Langerhans'/Dendritic cells. 3)Langerhans'/Dendritic cells then migrate out of the epidermis to the local lymph nodes. 4)APC interacts w/Tcells leading to proliferation and the generation of memory Tcells. Elicitation- 1) Upon subsequent contact, some Langerhans'/Dendritic cells (LDC) migrate to local lymph node as before. Other LDC can present processed hapten-carrier to memory Tcells in skin. 2) Activated memory Tcells then secrete cytokines which induce release of inflammatory cytokines from other cell types. 3)Memory Tcells & inflammatory cells are recruited from the circulation via local chemoattractant cytokines & expression of adhesion mcls. 4) These cells migrate to the epidermis & elicit the characteristic local inflammatory response. |
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Term
| Describe the molecular actions & functions of the PPARs. What types of PPARs are there? |
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Definition
| Actions: 1)Bind to fatty acids in cytosol or prostiglandins or AA. 2) dimerize to another receptor in cell (retinoic acid X Receptor-RXR)->gene expression; Functions: PPRa-enzymes: fatty acid oxidation & break down, break down of cholesterol, PPRb-not much is known..., PPRgamma-stimulate fatty acid synthesis & lipid accumulation, decr mitochodrial respiration |
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Term
| What are the mechanisms of PPAR disruption? |
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Definition
| 1)H2O2 induction: a by product of FA oxidation, PPRa agonists incr amt of FA oxidation enzymes, incr amt of perosomes in cell (H2O2->OH- + OH-*...the free radical indirectly causes DNA damage!) 2) Cellular proliferation (can cause cancer): stimulate TNFa-NFKb or MAPK pathways-> cell division, TZDs-treat Type II diabetes (cells insulin resistant bc cell doesn't produce glucose receptors) bc they decr insulin resistance, incr glucose receptors, stimulate PPRg->stimulate Acetyl CoA production, BUT can lead to proliferation of apidocytes (fat cells) in bone marrow, or fatty liver (fat accumulation in liver) |
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Term
| What is endocrine disruption? Describe the general mechanisms whereby toxicants or drugs can effect the endocrine system. |
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Definition
| Def: malfunction of the endocrine system (secretes hormones) due to xenobiotic exposure, best studied steriod & thyroid hormones. Mech of disruption: inhibit production of hormones (hmns), inhibit action of hmns, mimic hmns, alter metabolism of hmns |
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Term
| Describe the synthesis of cholesterol & seriod hmns. (only in as much detail as covered in class) |
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Definition
| Cholesterol: Acetyl CoA->AcetoAcetyl CoA->HMG-CoA (thru HMG synthase)->->->Squalene Epoxide->lanosterol->ergosterol(fungi) or cholesterol (animal) Steroid: Cholesterol->progesterone ->->corticosterol->aldosterone OR progesterone->->OH-progesterone-> cortisol OR testosterone->estradiol (estrogen) |
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Term
| What are the pharmalogical implications of modulating PPARs? |
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Definition
| Modulation of PPR by xenobiotics: Toxicants: phthalates-plasticizers->makes plastics sorter/ore flexible, bind to PPRa-agonists (start PPRa process); Drugs: Fibrate-stimulate fat breakdown and decr cholesterol |
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Term
| What steps of cholesterol synthesis can be affected by drugs, and for what diseases? |
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Definition
| HMG-CoA Synthase is inhibited therefore stops the synthesis of cholesterol (Lipitor); antifungals & antidermatophyte meds inhibit lanosterol formation out of Squalene Epoxide or ergosterol formation out of lanosterol |
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Term
| What is the role of the StAR protein in toxicology & steriod synthesis? |
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Definition
| Rate limiting step=transport of cholesterol into mitochondria..StAR ptn transports cholesterol into mitochondria,'squeeze' inner & outer mitochondrial membranes together, cholesterol: cytoplasm->mitochondrial matrix, certain pesticides (DDT, organophosphates) inhibit StAR ptn. |
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Term
| Discuss the general mechanism of steroid receptor binding & gene activation. |
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Definition
| diffuse thru membrane, nucleus bind to steroid receptor inactive state, bound to chaperone ptns (heat shock 90); Ligand binding-HsP90 dissociate, Steroid receptors (SRs) dimerize bind to steroid-responsive element initiating gene expression. |
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Term
| What is the biological function of estrogen & progesterone. |
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Definition
| Both are female sex characteristics: ovulation & menstral cycle, progesterone-maintaining placental integrity (keeps being produced during pregnancy); Estrogen receptors-found in most tissues in both sexes, lactation & breast dev, maybe involved in breast & ovarian cancer |
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Term
| Discuss methods that drugs & toxicants can affect the estrogen receptor & androgen receptor. |
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Definition
| Estrogen: 1)Toxicants: DDT, phthalates, Bisphenol A (plasticizer) Dioxins; Estrogen agonists-xenoestrogen, have low affinity for estrogen receptor therefore ?health effects?, persist & bioaccumulate; 2) Drugs: birth control pills-estrogen & progesterone or mimics that inhibit production of FSH & LH (from pituitary gland & stimulates maturation & release of oocytes; tamoxafen-estrogen receptor antagonist->used in treatment of estrogen responsive cancers. 3)Other mech: ex:)PCB's stimulate steriod (estrogen) catabolism; Androgens: AR anatagonists, ex:) DDE (breakdown product of DDT)->prevents testosterone binding, prevents testosterone/AR translocation, inhibits DNA binding; ex:)Dr. Gillete & alligator penises (pesticide contamination); Other mech: stimulation of testosterone catabolism by PCB's etc. |
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Term
| What does the Aromatase enzyme do? Discuss examples of drugs & toxicants that can affect the function of Aromatase. |
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Definition
| Aromatase (CYP19) converts testosterone into estradiol. Some chemicals stimulate aromatase, ex:) some herbicides->Atrazine (used a lot in corn causes feminizaion in male fish & frogs), inhibit phosphodiesterase (cAMP->AMP), which incr cAMP pathways, incr'ing aromatase; DRUGS: Aromatase inhibitors decr estradiol, treatment in breast and ovarian cancer. |
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Term
| What are the consequences of sex steriod disruption? |
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Definition
| feminization & demasculinization of fish & wildlife; decr fertility; cancers: breast, ovarian, testicular, prostate; developmental effects |
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Term
| What are corticosteroids? What are their functions? How do they affect immune function? What pharmacological uses for corticosteroids? How do toxicants affect corticosteroid production, & what is the consequences? |
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Definition
| DEF: cortisol & corticosterone (naturally); cortisone, prednisone (artificial); adrenal gland; bind to glucocorticoid receptor (GR); FUNCTIONS: anti-inflammatory; decr histamine secretion from mast cells, produced in response to stress (physical, emotional)->'fight or flight' response, incr glucose metabolism, incr glucose production from fats-glycogen, incr sensitivity to adrengeric receptors; IMMUNE: decr TNFa action & secretion, decr cytokine (e.g. IL) production, which decr Tcell activity natural regulator of immune function; DRUGS: anti-inflammatory/antihistamine-cortisone, prednisone; immune-suppressant drugs-transplant, autoimmune diseaes ex:) rheumatoid arthritis; TOXICANTS: chemical stress-> incr corticosteriod, which leads to immunosuppression OR dibutyltin from tributyltin binds to GR, antagonist |
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Term
| How is aldosterone production regulated? What is its function? What types of drugs can be used to modulate the rennin/angiogensin/aldosterone pathway, & for what purpose? |
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Definition
| PROD: lo BP or lo salt level-> kidney cells-> renin->angoitensinI->(ACE-Angiotensin converting enzyme)->angiotensin II->vasoconstriction OR adrenal gland-> aldosterone; FUNCT: incr Na+ & H2O reabsorption in kidneys-conserve H2O & salts, incr BP, distal tubule & collecting duct; Binds to mineral corticoid receptor (MR); DRUGS: BP pressure regulators-ACE inhibitors, aldosterone receptor inhibitors, angiotensin receptor inhibitors (cell surface receptor) |
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Term
| How does lead affect aldosterone production, and what are the consequences? |
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Definition
| Pb increases BP and therefore increases aldosterone production; stimulates corticosterone-> aldosterone |
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Term
| What is thyroid hormone composed of? Where & how is it synthesized? |
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Definition
| STRUCTURE: synthesized from tyrosine; connects 2 phenyl rings from adjacent tyrosines & adds iodide; 2 rings inner & outer rings; T4 has 4 iodides (thyroxine), also is more abundant in the body, T3 iodides (rT3=reverse T3-an inactive form) are more biologically active than T4. SYN: 1) Import of iodine: follicle epithelium imported I- from blood thru Na+/I- symporter; 2) Iodination of thyroglobulin (TG): thyroid peroxidase-uses H2O2 to make I radicals, 2 Iodinated Thyroid rings fused, and TG secreted & stored in colloid; BREAKDOWN: of TG & excretion of TH: epithelial endocytize TG, protease releases T4 and is secreted into blood stream |
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Term
| What are the functions of thyroid hormone, & consequences for TH disruption? |
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Definition
| FUNCT: Stimulates mitochondrial respiration & fatty acid oxidation, control growth-interact w/growth hormone, mood & behavior, essential for testicular function, interact & cross-talk w/sex hmns, embryonic dev; DISR: altered metabolism & growth, male infertility, altered mood & irritability, lethargy, sexual dev (in fish/amphibians), mental dev. |
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Term
| Discuss the hypothalmic/pituitary control & feedback of TH production. |
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Definition
| This is a neg feedback mechanism. First, the hypothalmus releases tyrotropic releasing hmn (TRH) to the pituitary gland, then the pit. gland releases thyroid stimulating hmn (TSH) to the thyroid. The thyroid then releases T4 & T3 to the target cells. T4 also can negatively feedback to the hypothalamus or the pituitary gland. |
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Term
| How is the thyroid hmn receptor activated? |
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Definition
| Action of TSH-peptide receptors-cell surface G-ptn via cAMP: induces TG-T4; stimulates follicular epithelial to grow & divide; lo TH-> incr TSH-> growth & hyperplasia of follicular epithelia. Transport of TH uses trans thyrein (ptn) in blood. |
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Term
| Describe the types of deiodinases & their functions. |
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Definition
| Act on thyroid gland & target tissues. FUNCT: remove I from T4 & T3; activate T4 & T3; inactivate T4->rT3 & T3->T2; TYPES: Type I- both activators & inactivators, Type II- activator->deiodinates outering, Type III- decativators bc they deiodinates inner ring |
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Term
| Describe the mechanisms whereby various drugs & toxicants disrupt TH production or action. |
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Definition
| DISRUPTION of TH homeostasis: 1) Blockage of I import-ex:) perchlorate (ClO4-) blocks Na+/I- symporter, oxidizer in rockets & flares; 2)Inhibition of thyroid peroxidase-ex:) thiocarbamate (fungicides), decr fertility in banana workers, ?thyroid cancer in rural areas? 3) Blockage of binging to transport ptns-binding to transtyretines, PCB (poly chlorniated biphenyls), brominated flame retardant; 4) binding to TR-Antagonist->amiodarone is a anti-arryhymtic drug & Agonists would be some triazine herbiides; 5) Inhibition of deiodinase activity-ex:) heavy metals prevent activation T4->T3; 6)Stimulation of TH metabolism-PCBs, dioxin, PAH, induced enzymes that metabolize THs |
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Term
| What is biotransformation? What are the outcomes & types of biotransformation reactions? |
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Definition
| DEF: enzymatic alteration of chemicals; OUTCOMES: inactive-less toxic OR bioactivation-more toxic; TYPES: phase I metabolism-oxidation/reduction; phase II metabolism-conjugation of phase I metabolites |
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Term
| Describe 3 types of Phase I enzymes. |
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Definition
| Flavin-containing monooxygenases (FMO), Epoxide hydrolases, & Monoamine oxidases (MAO) |
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Term
| What is the function of cytochrome P450 enzymes? What reactions do they catalyze? |
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Definition
| to reduce hydrocarbon reactions???? The cycle: CYP-> (via NADPH->NADP (P450 reductase)) and addition of O2 & R group) R-CYP-O2- -> (via NADPH->NADP (P450 reductase) R-CYP-O2-2-> (via 2H+ -> ROH + H2O)-> back to CYP; RXNS:?????? |
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Term
| Describe the nomenclature of cytochrome P450 enzymes, regarding their families & subfamilies. |
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Definition
| Families: ex:) CYP1, CYP2, CYP3, etc. Subfamilies: ex:) CYP1A, CYP1B, CYP2A, CYP2B, etc. Isoforms: ex:) CYP1A1, CYP1A2, etc. |
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Term
| Describe how P450 enzymes can activate toxicants. |
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Definition
| Epoxide formation: R-C=C-R -> R-C/0\C-R (R-C-> DNA & C-H-> ptns) aromatic, cyclic, aliphatic, epoxides; Reactive aldehydes: pentamer aromatic ring w/ one Oxygen -> hexamer aromatic ring w/2 Oxygens bound together; Activate Nitrosamides: ring w/ R bound to R w/ an N bound to both R's,then that N is connected to an N=O group -> RCHO aldehydes + N2+R2 (DNA); rubber manufacture, insecticide manufacture, hot dogs |
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Term
| Discuss how activation or inhibition of cytochrome P450 enzymes can be involved in drug-drug, toxicant-toxicant, or drug-supplement interactions. |
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Definition
| DRUG-DRUG: erythromycin inhibits CYP3A4, which leads to decr clearance of 3A4-metabolized drugs, which leads to incr bld levels, which leads to overdose. TOXICANTS-TOXICANTS: ex:)heavy metals inhibit CYP1A1, which decr clearance of dioxins. DRUG-SUPPLEMENT: ex:) grapfruit juice contains Bergamotin->inhibits CYP3A4-don't take Lipitor w/grapefruit juice. Also St. John's Wort-herbal supplement that induces drug metabolizing CYPs, therefore decr effectiveness |
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Term
| Discuss the following phase I enzymes in terms of what they do, their functions, & how they are involved in bioactivation and/or drug-drug interactions: Flavin-contaning monooxigenases, epoxide hydrolases, monoamine oxidases |
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Definition
| Flavin-containing monooxigenases: Flavin is a cofactor derived riboflavin, different isoforms FOM1, FOM2, FOM3, etc. (they are found in the sER); Function-oxides chemicals w/S, N bound RS->RSOH & RN->RNOH; Bioactivation-thiourea (used to make thiocarbamate->makes pesticides) Mech: HN=Cw/2 SH groups coming off of it-> (via FMO) R-SO2H, which goes to DNA or ptns; Epoxide Hydrolases: Function-detoxify epoxides R-C/O\-R-> R-C(OH)-C(OH)-R; bioactivation- procarcinogenic PAHs, ex:) benzo(a)pyrene BaP *mech: BaP->(via CYP1A1)-> BaP epoxide-> (via Epoxide Hydrolase, EH) BaPdiol->(via CYP1A1) BaPdiol epoxides (potent carcinogen bc binds to DNA->mutations; Monoamine Oxidases (MAOs): found on outer mitochondrial membrane, esp. liver; R-NH2-> R-NH-OH, also found in synaptic cleft of synapses; Function-deactivate NTs, ex:)dopamine, serotonin, epinephrine;metabolize drugs inside cells that happen to be monoamines. Inhibitors: drugs-MAOI-used to treat anxiety, deression; interactions-decr clearance of certain drugs, which leads to an incr in blood levels, ex:) difenhydrmine & antihistamine |
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Term
| Give examples of 'famous' cytochrome P450 enzymes. |
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Definition
CYP1A subfamily: CYP1A1-metabolize PCBs, dioxins, PAHs, (aromatic rings); bioactivate aflotoxin-molds (grains, peanuts); cancer, liver damage; procarcinogen; CYP1A2: tylenol, caffeine, stradiol, naproxine (aleve); CYP2 family: metabolizing MANY DRUGS; CYP2D6, CYP2C9, CYP2C19-codine, beta blockers, NSAIDs, barbituates, valium, and many others; CYP3A4: very wide array of drugs-statins, tylenol, codeine, SSRI, sedatives (valium)
BASIICALLY: 1)RX→RXOH, where X=N,S;
2)RX→R, X=NO2, S, O; 3)RX→ROH, X=F, Cl, Br; 4)R→ROH; 5)R-CH=CH-R → R-CH-CH-R epoxide (C-O-C) |
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Term
| Explain how cytochrome P450 genes can be activated by the aromatic hydrocarbon receptor, PXR, and CAR. |
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Definition
| Aromatic Hydrocarbon receptor(AHR): (PCBs dioxins, PAHs) HSP90's come off, AHR binds; AHR nuclear translocator (ARNT) in the nucleus, dimerizes & binds to xenobiotic reponsive element (XRE); Pregnane X receptor (PXR): binds to ligand (e.g. drug) in cytoplasm->nucleus; dimerizes w/RXR, binds to promoters of e.g. CYP3A4; Constitutively active receptor (CAR): does not bind ligands; inducer ex:) phenobarbitol, stimulates dephosphorylation in cytoplasm; nucleus is rephosphorylated (diff site), dimerizes w/RXR binds to phenobarbitol responsive element, expression of CYP2 etc. |
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Term
| What do phase II enzymes do? What are their roles in excretion, and how do they compare with phase I enzymes with regard to activation (toxification) vs. inactivation (detoxification) of drugs & toxicants. |
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Definition
| Function: add H2O soluble conjugates to phase I metabolites to make them more H2O soluble. Role in excr: conjugates excreted in urine & bile & then transported by export pumps (liver) via the p-glycoprotein MATE OR via OAT kidney. Compare: balance of Phase I & II is important. Phase I>phase II-bad, phase I less phase I & more phase II |
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Term
| What is glutathione? What does glutathione transferase (GST) do? What types of phase I metabolites are preferentially conjugated by glutathione transferase? |
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Definition
| Glutathione is a tripeptide mostly composed of glumate-cysteine-glycine. GST detoxifies epoxides, hyperoxides, & other electrophiles, which are attracted to nucleophilic sites on ptns. GST is primary enzyme for detoxification of BaP diol epoxide. |
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Term
| Describe 2 examples of how GST can be involved in bioactivation of xenobiotics. |
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Definition
| 1) Halogenated hydrocarbons: ex:) ethylene dibromide (insecticide, fumigant) is converted to a triangular positively charged GS molecule, which can then bind to DNA & ptns. 2) Tricholorethylene (solvent): bioactivated by GST to form Cl-C=C=S, which can then bind to DNA & ptns. |
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