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NST 11: Introduction to Toxicology

by: Carolyn Smullin

NST 11: Introduction to Toxicology NST 11

Carolyn Smullin
GPA 3.78

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A compilation of notes from a semester course in General Toxicology. The course was divided into three "units", with a midterm concluding each unit. The notes are divided reflecting that structure.
Introduction to Toxicology
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This 22 page Bundle was uploaded by Carolyn Smullin on Thursday February 4, 2016. The Bundle belongs to NST 11 at University of California Berkeley taught by in Winter 2016. Since its upload, it has received 47 views. For similar materials see Introduction to Toxicology in Natural Sciences and Mathematics at University of California Berkeley.

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Date Created: 02/04/16
NST 11: Midterm #1 Study Guide Lectures 1, 2, and 3: 1) Definition: the study of the negative effects of chemical and physical agents on living organisms. 2) Most exposure of humans to chemicals is via naturally occurring compounds consumed in the diets from food plants. 3) Chemicals are natural, biological, or synthetic in origin: a. Natural (food, metals, minerals) b. Biological (toxins from bacteria) c. Synthetic: manufactured through chemical processes 4) Most toxicologists work to assess and understand how chemicals af fect living systems. 5) Mechanistic Toxicology: chemical research in toxicology usually investigates metabolic transformations of drugs or potentially hazardous chemicals. 6) Descriptive Toxicology: typically involves toxicity testing. 7) Toxicity testing: assesses the concentration-dependent hazard a chemical may present. a. Broad spectrum of responses reflects toxicity: i. Functional effects, such as immunological responses. ii. Growth inhibition iii. Reproductive impairment iv. Increase in cancer incidence v. Mortality 8) Types of toxicity testing: a. In vitro (test tube): useful in detecting potential biochemical and genetic effects. i. Use model systems (bacteria, cultured animal cells, DNA interactions). b. In vivo (animal): are essential for detecting health effects i. Acute, chronic, multi-generation ii. Experimental animals may be treated with high doses over a lifetime to evaluate potential to cause cancer. c. In silico (computer-based): biological experiments conducted by computer models; these depend on data previously collected in other experiments. 9) Regulatory Toxicology: setting rules and assuring compliance. a. Product registration b. Allowable concentrations in food or environmental media c. Risk and safety are estimated by total weight of evidence. 10) Translational science: the application of biomedical research and drug development to efficiently use a promising drug in the right patient circumstances and assess its efficacy in the human using appropriate indicators such as biomarkers. 11) Fundamental concept of toxicology: dose determines toxic effect. a. In any given population, there will be a range of sensitivities to a xenobiotic. b. The magnitude of the toxic response to a xenobiotic is proportional to the concentration of the chemical at the target site. 12) Four important processes control the amount of a chemical that reaches the target site: a. Absorption b. Tissue distribution c. Metabolism d. Excretion 13) Dose-Response Relationships: a. Effective Dose (ED): therapeutic dose of a drug b. Toxic Dose (TD): dose at which toxicity arises c. Lethal Dose (LD): dose at which death occurs d. NOAEL: no observed adverse effect level i. Occurs where the curve for Therapeutic Dose begins e. LOAEL: lowest observed adverse effect level i. Occurs right where the curve for Lethal Dose begins f. Threshold: dose below which no effect is seen (beneficial vs. adverse) g. ED50: dose at which 50% of a population therapeutically responds h. TD50: dose at which 50% of a population experiences toxicity i. LD50: dose at which 50% of a population dies 14) Hormesis: a response that is beneficial at low doses but toxic at higher doses. a. Ex: alcohol and vitamins. b. The graph for a chemical that is beneficial at low doses but toxic at high doses is an upside down parabola. 15) MS (certain safety factor): LD1/ED99 16) Risk depends on hazard, dose-response levels, and exposure assessment. 17) Absorption occurs by: a. Diffusion of fat soluble substances through lipid membrane b. Diffusion of water-soluble substances through pores c. Active transport of some types of both water -soluble and lipid-soluble substances through membranes. 18) Circulatory System: a. Hepatic/portal circulation: passage of substances from the gut through the portal vein to the liver. b. Biliary circulation: can result in enterohepatic circulation. c. Lymphatic circulation into blood: pass age of substances in the lymph via the thoracic duct to the left subclavian vein- can result in lung specific toxicity from ingested toxins. d. “First pass” metabolism: involves metabolism of an ingested xenobiotic before it reached the general circulation. 19) Storage sites: a. Protein in blood: polar substances b. Liver and kidneys: many metals such as cadmium c. Fat (adipose tissue): lipid soluble substances d. Bone: meals such as lead and strontium 20) Effects of storage on toxicity: a. Decrease toxicity: if storage site is DISTANT from site of action b. Increase toxicity: if storage site is site of action 21) Excretion- active and passive a. Kidney to urine: most important for quantity b. Liver to bile: metals c. Intestine to feces: mostly unabsorbed, some active d. Lunge to expired air: volatiles, gases e. Mammary gland to milk: lipid soluble xenobiotics f. Exocrine glands to swear, saliva etc.: water -soluble xenobiotics 22) Chemical factors that determine toxicity: a. Lipid solubility: lipid soluble substances cross lipid membranes easily b. Biotransformation: i. Phase 1 metabolism: a chemical “hook” is added to the xenobiotic by oxidative enzymes in cells. ii. Phase 2 metabolism: a water soluble “tag” chemical is added to the hook from phase 1 metabolism to make the metabolite more water soluble. c. Metabolic activation: a biologically inactive precursor chemical is converted by enzymes in the body into a form that will react in the body. d. Regulation of metabolism: the expression and activities of xenobiotic metabolizing enzymes in the body can be regulated by the toxin or by other less toxic substances in the environment and food. 23) Some chemical are partially converted to products that are more toxic than the parent substance 24) The cytochrome p450 superfamily (CYP) catalyze the oxidation of organic substances (phase 1 reaction). The substrates for CYP include lipid metabolites, steroid hormones, and xenobiotics such as drugs and toxic chemicals. Lectures 4, 5, and 6: 1) Ethanol: a. 20% of ethanol is absorbed into the bloodstream directly from the stomach and 80% from the small intestine. b. Ethanol is highly water-soluble and is absorbed much less in fat, which is why it tends to distribute itself mostly in tissues rich in water (muscl e) instead of those rich in fat. i. Women and elderly are more sensitive to ethanol because of increase body fat compared to men. 2) Mode of action of ethanol: a. Alcohol increases the effect of GABA (inhibitory neurotransmitter). b. Reduces nerve signal flow in t he brain, 3) Anatomy of Nervous System cells: a. Dendrites: receive messages from other cells. b. Axon: passes messages away from the cell body. c. Terminal branches of axon: from junctions with other cells. d. Synapse: specialized junctions through which neurons signal to each other and to non -neuronal cells such as those in muscles or glands. 4) Chemical transmission requires: a. Synthesis of neurotransmitter in the presynapse b. Storage of the neurotransmitter in secretory vesicles c. Regulated release of neurotransmitter into the synaptic space d. The binding of release neurotransmitters to post -synaptic receptors to propagate neurotransmission e. A means for terminating the action of the released neurotransmitter 5) Metabolism of Ethanol: a. Ethanol --(ADH)à acetaldehyde --(ALDH)à acetic acid i. Happens in many tissues ii. Asians: lack of ALDH b. Ethanol –(CYP2E1)à acetaldehyde –(CYP2E1)à acetic acid i. Located in the ER of liver cells ii. Habitual drinking induces CYP2E1 activity c. Ethanol’s hydrophobicity allows it to diffuse across membranes eas ily and its hydrophilicity allows it to dissolve in the blood easily. 6) There is no safe level of alcohol for pregnant women. 7) Beneficial effects of ethanol: antioxidants, an increase in HDL cholesterol and anti -clotting properties. 8) Ethanol and Breast Cancer: a. Drinking alcohol increases blood estrogen levels, which in turn augments the risk of breast cancer. b. Drinking alcohol decreases folic acid levels in cells, which is important for DNA repair and replication. 9) Caffeine mode of action: a. Almost all organ systems can be influenced by caffeine b. The predominant sites of activity involve the CNS and cardiovascular system. c. Caffeine blocks receptors of adenosine. The general effects of adenosine in the brain is to inhibit neural activity, where as the effects of caf feine is to increase neural activity. In the heart, inhibiting adenosine receptors elevates cAMP in cells, which increases heartbeats. d. Caffeine also inhibits an enzyme, cAMP phosphodiesterase, which decreases cAMP levels in cells. e. Increasing cAMP in stomach cells elevates the secretion of gastric acid. 10) Caffeine toxicity: death from ventricular fibrillation with blood levels greater than 100 micrograms/ml 11) Smoking and disease: a. Approximately 90% of lung cancer is due to smoking. b. All long-term smokers get some level of chronic obstructive pulmonary disease, emphysema being the most serious. 12) Nicotine pharmacology: a. Biphasic action on acetylcholine receptors in CNS i. Agonist at low doses-stimulates ii. Antagonist at high doses - depresses b. Nicotine stimulates release of dopamine in reward centers of the brain (mesolimbic pathway) c. Nicotinic acetylcholine receptors are neuron receptor proteins that signal for muscular contraction upon a chemical stimulus. i. In CNS it is important for synaptic communication and excites brain. d. Tolerances: i. Develops rapidly within the first exposure for some effects. ii. Smokers clear nicotine faster than non -smokers e. Dependence: one of the most dependence -producing drugs i. Stimulates reward center in brain ii. Function: weight control, coping with stress iii. Social factors: can reduce stress of social situations f. Withdrawal systems: i. Lethargy-decreased arousal, constipation, headaches, disrupted sleep cycles, irritability/anxiety, and excessive hunger g. In utero exposures to nicotine result in: i. Increased risk of obesity, hypertension in child ii. Decreased birth weight iii. Increased motor, sensory, cognitive deficits iv. Increased attention deficit disorders Lecture 7, and 8: 1) Definitions: a. Neoplasm: heritably altered, relatively autonomous growth: can be benign or malignant. b. Cancer: malignant neoplasm (metastatic) c. Tumor: space-occupying lesion that may be benign or malignant. d. Mutation: heritable change in DNA 2) Phases of cancer: a. Initiation b. Promotion c. Progression 3) Tumorgenesis: a. Carcinogenàinitiationàpromotionàtumor formation 4) Steps in chemical carcinogenesis: a. Precarcinogenà activated carcinogenàinitiationàpromotionà progressionàmetastatic cancer 5) The production of the activated carcinogen depends on: a. The level and site of absorption of the pre -carcinogen b. The translocation of the pre -carcinogen to the site of metabolism c. The balance of phase 1 (activating) and phase 2 (deactivating) metabolism d. The efficiency of excretion of the metabolites 6) Initiation of cancer requires: a. A change (mutation) in the DNA sequence that encodes a gene important in cancer. i. Tumor suppressor gene: p53, protects cell from the path to cancer ii. Oncogene: Ras, Src, cause cancer b. This change is fixed in the genome by division of the affected cell. 7) Promotion: a. Results in the proliferation of initiated cells. b. Does not involve further changes to DNA. c. Caused by abnormal responses to normal proliferative agents such as hormones. d. Caused by continuous exposures to proliferative agents that induce toxic stress. e. *inflammation* 8) Progression: a. Results in the spread (metastasis) of the tumor cells to other organs. b. Caused by further mutations in genes that control the body’s defenses to tumor cells and the development of new blood vessels for the tumor. 9) Angiogenesis: the physiological process through which new blood vessels form from pre -existing vessels a. VEGF: vascular endothelial growth factor 10) NAS Recommendations: a. Reduce fat intake to <30% of calories. b. Eat more fruits, vegetables and whole gra ins: 9 servings/day c. Eat less food preserved by salt -curing or smoking d. Minimize contamination with carcinogens e. If you consume alcohol, do so only in moderation and without smoking. 11) Dietary carcinogens: a. Polycyclic aromatic amines (PAA): fried meats b. Polycyclic aromatic hydrocarbons (PAH): broiled, smoked meat c. Aflatoxins: peanuts, corn, etc. 12) More Dietary carcinogens: a. Nitrosamines: nitrite + amines b. Safrole: sassafrass c. Pyrrolizidines: comfrey tea d. Hydrazines: mushrooms 13) Natural antioxidants in foods: a. Citrus oils: limonene in citrus oil, blocks tumor development b. Polyphenols: present in food plants and tea, show protective effects against several cancers c. DIM: produced from 13C in Brassica plants, appears to be most active against mammary cancer and activates the immune system 14) More anti-carcinogens: a. Lycopene: present in tomato products, is associated with decreases prostate cancer. b. Allylsulfides: present in garlic and leeks, are associated with decreased cancers of several sites and show preventative activities. c. Isoflavones: substances present in soy, may decrease prostate and breast tumor incidence when consumed over a lifetime. Short term consumption of these substances increases cancer. 15) Oncohormesis: a. Low doses of radiation increase the biological defenses to subseq uent higher doses of radiation in vitro and in vivo b. Ischemic pre-conditioning induces the expression of neuro -protective factors. c. Phytochemicals may also function to protect normal cells from carcinogenic processes by hormetic mechanisms. i. Activate cellular stress-response pathways resulting in the up -regulation of protective gene products. 16) Answers to questions: a. Mutagens are not always carcinogens. Initiation caused by mutagens is only the first step in carcinogenesis. b. A cancer initiator causes a heritable change in DNA of a growth-related gene and a cancer promoter induces the growth of the initiated cell. c. Carcinogens from fried beef and the aflatoxins appear to be the most important human carcinogens in foods. d. Diets rich in protective substances from fru its, vegetables and whole grains and those low in fat are associated with decreases cancer rates in humans. NST 11: Midterm #2 Study Guide Lectures 1-2: Neurotoxicology 1. Neurotransmission a. Signal is received by dendrites, enters the cell body, travels down the axon, and is released by terminal branches to the synaptic space. b. Action potential: depolarization caused by an opening of Na channels and a flux of Na into the cell making membrane potential less negative 2. Membrane Potential a. Resting – inside of the cell is negatively charged (less Na and Ca) b. Excited – Na and Ca channels open and let positive ions enter the cell, depolarizing it (making the membrane positive) c. Restoration – ATP pushes 2 K into the cell and 3 Na out of the cell 3. Neurotransmitters a. Acetylcholine i. Binds Na channels; excitatory; increases permeability of ligand gated Na channels ii. binds nicotinic and muscarinic Ach receptors; excitatory iii. Nicotinic – receptors on parasympathetic neurons; raises cAMP levels iv. Muscarinic – receptors on cholinergic neurons; causes influx of Na into cell v. Controls motor and memory function vi. Degenerated by AchE into acetate and choline b. Glutamate i. Ca channels; excitatory c. GABA i. Opens up Cl channels ii. Chlorine enters cell and repolarizes it (inhibitory) 4. Neurotoxins that act on Acetylcholine a. Organophosphate (OP) inhibits AchE irreversibly, causing accumulation of Ach at synapse, hyper stimulating receptors, leading to convulsions, paralysis, death b. Fasciculin II (FAS II) i. From green mamba venom ii. Reversible inhibitor of AchE c. Galantamine i. Sourced from plants ii. Inhibits AchE iii. Used to treat Alzhiemers (memory loss associated with a loss of Ach producing neurons, stopping AchE preserves Ach, preserving memory) d. Epibatidine i. Found on skin in Ecuadorian frog ii. Stimulates nAchR, causes paralysis e. Nicotine i. Stimulates nAchR 5. Neurotoxins that act on Voltage gated Na channels a. Tetrodoxin i. Produced by puffer fish ii. Binds to and permanently close v.g. Na channels 6. Neurotoxins that act on Opioid recpetors a. Background: i. endogenous opioids are peptides produced in brain during exercise, sex, pain, etc. cause pain relief and well being ii. opioid receptor stimulation inhibits Ca channels, suppressing neurotransmission b. Heroin i. Synthesized and metabolized into morphine ii. Stimulates opioid receptors 7. Psychomotor Stimulants a. Cocaine and amphetamines b. Biphasic action: i. stimulants at low doses ii. inhibit uptake of dopamine, serotonin, and norepinephrine. Increase their levels at the synapse. Cause hyper stimulation. iii. Epi and NE bind to adrenergic receptors (fight or flight response). Cocaine overstimulates this signaling. c. Mechanism of Reinforcement i. Heightened dopamine levels leads to desensitization of dopamine receptors ii. Stimulates reward center of brain 8. Neurodegeneration a. Process mediated by reactive oxygen stress: increase stress àdecrease ATP àincrease Ca b. Caused by repeated exposure – damage to nerve endings c. Cyanide i. inhibits cytochrome oxidase (complex IV in the electron transport chain) in the mitochondria and inhibits ATP formation. d. MPTP i. Contaminant in MPP à crosses blood brain barrier and is metabolized by MAOB into toxic MPP+ à MPP+ taken up by dopamine transporters à MPP+ inhibits complex 1 of the ETC and depletes ATP ii. Antidote – seregilin (MAOB inhibitor) 9. Parkinson’s a. possibility that the onset of a neurotoxic problem may follow toxic exposure by many years b. Parkinson’s Disease has a greater environmental component (95 %)than genetic component c. Symptoms develop after 80% of substantia nigra neurons are lost d. Possible environmental agents: i. Metals, pesticides, insecticides, herbicides ii. Rotenone is a broad-spectrum insecticide that inhibits complex I of the electron- transport chain. i. Paraquat is a potent herbicide that produces oxidative stress similar to that of MPP+ Lectures 3-4: Marijuana to Cannabinoid-Based Therapies 1) Background a. Derived from the cannabis sativa plant. b. The active component of Marijuana is delta-9-tetrahydrocannabinol (THC) c. Marijuana Effects: mild euphoria, relaxing “high,” increased appetite, cognitive impairments related to attention and memory, and motor impairment. 2) Beneficial effects of cannabinoids: a. Cannabinoid-based pharmaceuticals: Dronabinol (capsules of THC), Cesamet (THC analog nabilone). b. Prescribed for: i. Vomiting and nausea in cancer patients ii. Prevention of weight loss in AIDS patients iii. Reducing pain and spasticity in multiple sclerosis iv. Phase 1-3 for cancer anorexia, pain, depression and anxiety c. Shown efficacy in rodent models of: i. Pain, stress, inflammation, anxiety and PTSD ii. Dyskinesia in Parkinson’s disease iii. Reducing intraocular pressure in glaucoma 3) Psychotropic effects of cannabinoids a. through cannabinoid CB1 receptors, which are G- protein coupled receptors. b. Are highly expressed in the brain. 4) Mechanism of cannabinoid-mediated “high:” a. THC bind to CB1 receptors, which are part of a family of receptors called G- protein, coupled receptors (GPCR) and inhibits neurotransmission. b. Inhibits adenylate cyclase and reduces cyclic AMP (cAMP) levels à inhibits protein kinase A (PKA) activation and reduces the gene expression of CREB, leading to impairments in long term memory. c. Inhibits voltage-gated Ca+ channels à reduces neurotransmitter release from presynapse (ex: glutamate) à suppresses neurotransmission. 5) Brain regions that express the CB1 receptor abundantly: a. Cerebral cortex, prefrontal cortex, basal ganglia, hippocampus and cerebellum. 6) Effects of Spice: a. Exerts strong cannabis-like effects. b. Several cases of overdosing that require hospitalization. c. Produces a sense of empathy and well-being, euphoria, and disinhibit ion. d. Increasing number of cases involving emergency medical care after smoking Spice, including nausea, anxiety, agitation/panic attacks, tachycardia, paranoid ideation, hallucinations, psychosis, loss of consciousness and confusion, unresponsiveness, seizures, agitation and irritation. e. Ingredients found in Spice are synthetic cannabinoids that are 10-1000 x’s more potent 7) Endocannabinoids are retrograde messengers: a. They are synthesized in the post-synapse and bind to the pre-synpase CB1 receptor to inhibit NT release b. Endocannabinoids are 2-AG and anandamide, which bind to and activate CB1 c. They are synthesized in the post-synapse, released and bind to pre-synaptic CB1 receptors to inhibit neurotransmitter release. 8) Fatty acid amide hydrolase (FAAH) a. FAAH converts anandamide into arachidonic acid. b. FAAH inhibitors reduce depression, anxiety, vomiting, nicotine and opiate addiction. c. Genetic ablation of FAAH leads to reduced pain and inflammation without any cognitive side- effects. d. Pfizer and many other pharmaceutical companies have developed FAAH inhibitors and they have passed Phase 1 clinical trials and are in Phase 2 for pain and anxiety. 9) MAGL a. MAGL converts 2-AG into arachidonic acid. b. Selective MAGL inhibitor JZL184 raises brain 2-AG levels and lowers arachidonic acid c. MAGL inhibition enhances anti-inflammatory endocannabinoids and suppresses the pro- inflammatory eicosanoids. d. MAGL inhibition suppresses pain and inflammation and protects mice against neurodegeneration. 10)MAGL Inhibitors: a. Do not produce cognitive side-effects b. Suppress pain, anxiety, depression, fever (cannabinoid) c. Protects mice against neuroinflammation d. Reduce Parkinson’s Disease and Alzheimer’s Disease through reducing eicosanoids. e. Protects mice against liver damage and live fibrosis (cannabinois/eicosanoids) 11)Blocking both MAGL and FAAH produces full-blown cannabinoid effects. 12)Role of Cannabinoids in Food Intake and Energy Balance: a. Activation of CB1 receptors leads to increased food intake, adiposity, and insulin resistance b. Cannabinoids increase eating motivation and pleasures through stimulating dopamine release c. Cannabinoids increase preference for sweet and palatable foods. d. Activation of CB1 receptors favors energy intake and reduced energy expenditure. 13)Cannabinoid Receptor Antagonist Rimonabant: a. Induce weight loss by reducing food intake, reducing fats synthesis and storage, and increasing fat oxidation. b. Improve cardiovascular risks by reducing “bad” LDL-cholesterol and raising “good” HDL cholesterol. c. Improve insulin resistance and glucose tolerance and efficacious against type II diabetes. d. In 2006, a CB1 receptor antagonist (Rimonabant/ Acomplia) was approved for the treatment of obesity in Europe. e. Patients taking Rimonabant experiences psychiatric problems such as mood symptoms, anxiety, and suicidal tendencies. f. 2007: FDA did not approve Rimonabant. g. 2008: Europe discontinuous use of Rimonabant. Lectures 5-6: Pesticides and GMO’s vs. Organic Foods 1) Pesticide: any substance intended for preventing, destroying, repelling, or mitigating any pest. a. All pesticides possess an inherent degree of toxicity, and are not as selective as they should be 2) Why we need pesticides a. Pest losses must be reduced for maximum production. b. 1/3 of the world’s food crops are lost due to pests during growth, harvesting, or storage. 3) Insecticides: most insecticides are neurotoxicants and affect the nervous system and neurophysiology. 4) Types of Major Insecticides: a. Organochlorines: i. DDT (stimulates Na+ channels), ii. Polychlorocycloalkanes (GABA receptor antagonist) iii. Fipronil (GABA receptor antagonists) b. Pyrethroids: stimulate Na+ channels c. Organophosphate compounds: inhibits AchE d. Neonicotinoids: stimulate nAchR 5) DDT- first modern insecticide developed in the 1940s a. In insects: DDT causes tremors (DDT jitters) followed by paralysis and death in a few hours to days (topical LD50 is 27 micrograms/bee) from binding to and opening voltage-gated Na+ channels. b. Human/mammals: oral LD50- 300-350 mg/kg c. Acute exposure: i. At high oral doses, DDT results in paresthesia of tongue, lips and face. ii. Hypersusceptibility to external stimuli (light, sound, touch). iii. Irritability, dizziness, and vertigo; tremor and convulsions. iv. Symptoms arise 6-24 hours after exposure to large doses > 10 mg/kg d. Rachel Carson wrote “Silent Spring” and is credited for the ban of DDT in 1972. i. Claimed detrimental effects of DDT on the environment e. DDT is bio accumulative and biomagnifies in food chains i. In humans, DDT accumulates in fat and breast milk. f. DDT and Cancer i. is an endocrine disruptor: can bind and stimulate the estrogen receptor to cause aberrant cell growth ii. induces cytochrome p450s: result in oxidative stress and inflammation g. Declined use of DDT was due mainly to resistance developed quickly in many insects. i. Increased DDE enzyme to detoxify DDT. ii. Nerve insensitivity (mutation in the Na+ channel that confers DDT resistance- “knockdown resistance.” 6) Pyrethroids a. Considered the safest insecticide due to fast biodegradability b. Mode of action: Na+ channel agonist. i. Insect Na+ channels are 100-fold more sensitive to Pyrethroids than mammals. 7) Fipronil + Polychlorocycloalkanes a. Inhibits GABA receptor (GABA is inhibitory) b. Increases neurotransmission 8) Organophosphate Insecticides: a. The most widely used insecticide in chloropyrifos. i. Chronic exposure linked to neurological effects, developments disorders and autoimmune disorders. ii. Chloropyrifos has been banned in homes since 2001 in the US but is still heavily used in agriculture. b. Organophosphate nerve agents act by irreversibly inhibiting acetylcholinesterase. i. Stops the conversions of acetylcholine into acetate and choline. ii. Sarin binds to the AChE active site and inhibits its function. c. Effects of OP Insecticide Exposure in Humans: i. Increased respiratory problems-asthma, wheezing ii. Abnormal motor function and reflexes, weight gain, insulin resistance iii. Associated with Parkinson’s disease, neuroinflammation, and death of dopamine-producing neurons. iv. Many of these responses occur without inhibition of AChE in human populations indicating alternate mechanisms and toxicity in humans. 9) Neonicotinoids: newer class of insecticides a. Nicotinoids: Derived from nicotine i. Stimulate nAchR ii. Mammalian selective b. Neonicotinoids: next generation of insecticides derived from nicotinoid structures. i. Stimulate nAchR ii. Insect-selective iii. Effective at low application rates. Not environmentally persistent c. Nicotinoids have a positively charged tip and Neonicotinoids have a negatively charged tip. i. Insect nAChR binding pockets favor a negatively charged tip (Neonicotinoids) ii. Mammalian nAChR binding pockets favor a positively charged tip (nicotinoids) 10)Herbicides: any compound that is capable of either killing or severely injuring plants. a. Some of the very early chemicals, such as sulfuric acid, arsenic trioxide, copper sulfate were toxic and nonselective. b. Atrazine: used on corn for grassy and broad-leafed weeds. i. Mode of action: strong inhibitor of photosynthesis- selectivity depends on the ability of tolerant crops to metabolize the compound whereas susceptible plants do not. ii. Atrazine at low doses produces hermaphroditic/demasculinized frogs by inducing aromatase and promoting the conversion of testosterone to estrogen. iii. Atrazine may also lead to increases in reproductive cancers in humans. c. Glyphosphate (Roundup): broad-spectrum nonselective system herbicides for grasses, weeds and woody plants. i. Glycophosphate binds to and inhibits the enzyme EPSPS, an enzyme essential for protein synthesis in plants. 11)GMOs a. Roundup Ready corn engineered with BT gene for resistance to moth larvae and corn rootworm i. BR Cry toxins aggregate to form pores in the membrane of the insect gut causing cells to lyse 12)GMO Controversy: a. There is broad scientific consensus that genetically modified crops are safe to eat since transgenes from plants do not contaminate the human genome. b. There are large concerns over the following: i. Allergenicity: NO ii. Horizontal gene transfer: NO iii. Biodiversity: there is no evidence that GMOs alter microorganisms although insect selection can occur. iv. Gene flow: this is of concern since genetic material from GMOs can potentially contaminate neighboring non-GMO crops and plants- could also lead to genetically modified weeds. 13)Organic Foods: a. Foods produced using methods of organic farming that do not involve modern synthetic pesticides and chemical fertilizers, radiation, solvents, or food additive. b. Why are they not necessarily safer than non-organic foods? They are still grown with pesticides and fertilizers. One organic pesticide, Rotenone, is linked to Parkinson’s. Nicotine is also an organic pesticide, and it is very toxic to mammals (humans.) Lecture 7: Developing Safer Drugs 1. Preclinical development a. 6-7 years of preclinical testing b. Of 5000 compounds tested, ~5 will appear promising enough for a company to file an Investigational New Drug Application (IND) c. If the IND is approved, then the company can begin Phase I clinical trials 2. Steps: a. Efficacy: does it work? b. ADME Profiling and testing: test materials with respect to absorption, distribution, metabolism, and excretion (ADME). required: 2 species c. Safety/Pharmacology Assessment: to investigate any toxicity—use single dose with 2 species and test cardiovascular, respiratory, CNS effects 3. On and Off Target Toxicites a. On-Target Toxicity: Toxic effect due to the drug interacting with the intended therapeutic target b. Off-Target Toxicity: Toxic effect due to the drug interacting with an unintended biological target or unintended tissue c. Idiosyncratic drug reactions: drug reactions that occur rarely and unpredictably d. Idiopathic drug reactions: cause unknown 4. On Target Examples a. Rosiglitazone (or Avandia) i. It was prescribed as an insulin sensitizer for diabetics by binding to PPAR receptors in fat cells ii. causes on-target edema which can put people at risk for congestive heart failure b. Non-Steroidal Anti-Inflammatory Drugs (Aspirin, Ibuprofen, Diclofenac, Naproxen, acetaminophen) i. Used for pain relief, inflammation, fever reduction and swelling ii. all inhibit cyclooxygenases type 1 and 2 (COX1 and COX2) and reduce pro-inflammatory eicosanoids such as prostaglandins, prostacyclins, and thromboxanes iii. Nonselective COX1/COX2 inhibitors increase risk of gastrointestinal bleeding, because prostaglandins help to maintain the gut mucosal protective barrier (due to COX1 inhibition) c. Rofecoxib (Vioxx) i. COX2-selective inhibitor with very little gastrointestinal side-effects • ii. Prescribed as a pain reliever for arthritis iii. was found to be responsible for increased risk of heart attack and stroke iv. COX2 is responsible for synthesis of prostacyclins in the vasculature which are cardioprotective. COX2-selective inhibition reduces the cardioprotective prostacyclin and causes cardiac events d. Cerivastatin (Baycol) i. Prescribed to patients as a treatment for high cholesterol ii. Connected to severe muscle disorder known as rhabdomyolysis, which clogs the kidney with protein from dying muscle tissue e. Benadryl i. an antihistamine that antagonizes the H1 histamine receptor to reduce unpleasant symptoms of histamine release in allergic conditions. ii. Diphenhydramine also crosses the blood brain barrier where H1 histamine receptor antagonism causes sleepiness (modern day no longer does this) 5. Off Target Examples a. Terfenadine (Seldane) i. nonsedating antihistamine ii. Replaced by fexofenadine due to risk of cardiac arrhythmia iii. Terfenadine is a prodrug that is metabolized to fexofenadine by cytochrome P450 CYP3A4 iv. Terfenadine inhibits an off-target cardiac potassium channel (hERG). Inhibition of hERG led to fatal cardiac arrhythmias b. Thalidomide i. was an anti-nausea and sedative drug used to help with morning sickness ii. found to be a teratogen (causing severe birth defects such as phocomelia involving shortened limbs that looked like “flippers”) iii. Mode of Effect: Thalidomide was sold as a racemic mixture of R- and S-thalidomide. • R-thalidomide stimulates the GABA receptor to cause sedative effects. • S-thalidomide binds to a protein and inactivates a protein called cereblon which is important in producing proteins involved in limb outgrowth • R- and S-thalidomide can interconvert in vivo. iv. Thalidomide is now currently used for cancer therapy due to its anti-angiogenic properties NST 11: Midterm #3 Study Guide Lecture 1: Pharmacogenomics 1. Pharmacogenetics A. Study of Inherited Differences (Variation) in Drug Metabolism & Response 2. Pharmacogenomics A. Systemic genomic analysis in populations of treated subjects B. Study the influence of genetic s on drug responses i. Polymorphism: variation in the genomic sequence, largely responsible for differences between how humans respond to drugs (expression and activity of genes) ii. Single-Nucleotide Polymorphism (SNP): a DNA sequence variation commonly occurring within a population (e.g. 1%) iii. SNP in the coding region (exon) of a gene could affect the activity of the protein iv. SNP in the regulatory region (promoter, intron, enhancer) of a gene could affect the expression of the protein 3. Pharmacokinetics A. Plasma Clearance, Delivery of Drug or Metabolite to Target Cells 4. Pharmacodynamics A. The Relationship between the Drug Concentration & Its Therapeutic Effect B. The Likelihood of an Adverse Reaction 5. Pharmacogenomics Strategy Applied to the Practice of Medicine A. All patients with the same diagnosis: remove non-responders and toxic responders, treat responders and patients not predisposed to toxicity 6. Polymorphic P450s: Associated with Changes in Drug Effects A. CYP2C9 CYP2C19 CYP2D6 TPMT B. The correlation between phenotype and genotype for CYP3A is not fully understood 7. Mercaptopurines A. Used to treat Leukemia B. Mechanism i. Thiopurine methyltransferase (TPMT) converts mercaptopurine into an inactive metabolite called methylmercaptopurine ii. High TPMT: decrease therapeutic effect iii. Low TPMT: increase toxicity iv. Mercaptopurine-derived products are incorporated into DNA by hypoxyxanthine phosphoribosyl transferase (HPRT) and block DNA replication and lead to tumor cell death 8. Breast Cancer A. BRCA1 and 2 is a tumor suppressor gene that helps repair DNA damage B. Mutation in BRCA1 and 2 genes can result in defects in DNA repair and potentially cause cancer C. Specific inherited mutations in BRCA1 and 2 increase the risk of breast and ovarian cancer D. Mutations in BRCA1 and BRCA2 account for 5-10% of breast cancer (20-25% inherited breast cancer) and 15% ovarian cancer 9. What Makes Pharmacogenomics Possible? A. Advances in genome sequencing technology, Advances in bioinformatics, Sequencing human genome 10.Future Trends for Pharmacogenomics A. Population Screening , Population Sequencing, Personal Medicine, Personal Genetic Testing Lecture 2: Toxic Metals 1. Mercury A. Food Sources i. Extreme levels: Ahi tuna, shark, swordfish ii. High levels: canned albacore tuna, sea bass iii. Moderate levels: cod, halibut, mahi mahi iv. Low levels: crab, salmon, shrimp, tilapia v. FDA limit for fish is 0.5 ppm, most are at 0.3 ppm B. Environmental Sources i. Occurs as the sulfide red powder called cinnabar. Heating produces liquid mercury metal. ii. Natural out gassing of mercury iii. Combustion of fossil fuels C. Mercury cycle (SEE DIAGRAM) i. The chemical forms of mercury are interchangeable ii. The lipophilic form of mercury bio accumulates D. Uses i. Gold and silver mining ii. Paints, electrical switches, mercury vapor lamps, dental amalgams iii. Felt making (“mad as a hatter”) E. Toxic effects i. Hg+2 (weakly toxic, oral) 1) water soluble, binds proteins 2) (chronic) ultimately toxic to kidneys 3) (acute) GI upset, nausea, vomiting , bloody diarrhea ii. Hg (metallic, toxic by inhalation) 1) (chronic) neural excitability, tremors, gingivitis, memory loss 2) (acute) bronchitis, tremor, delirium, hallucinations 3) Formerly used as a laxative F. Methylmercury: potent neurotoxin (Minamata disease) i. Loss of motor control, Paralysis of limbs, Misshapened joint, Hallucinations, Delirium, Convulsions, Severe birth defects ii. Methylmercury induces oxidative damage in nerves G. Effects of low level Hg poisoning from marine organisms i. Studies conducted in the 1990s characterized in-utero exposure of children and followed their neurological development ii. The Seychelles study concluded that no adverse effect could be attributed to chronic exposure to methylmercury from fish iii. The Faroe Island study demonstrated negative developmental effects in high- exposure children compared to children in the low exposure groups iv. Differences in results not explained. One possibility is that the diet on the Faroe Islands consists primarily of marine mammals, whereas the Seychelles diet consists primarily of fish. Toxins in blubber might be involved H. Selenium i. Expression of both selenoprotein P and glutathione peroxidase (GSH-Px) ii. Protecting against Hg toxicity (oxidative damage) 1) They bind more Hg through their highly reactive selenol group 2) Their antioxidative properties help eliminate the reactive oxygen species induced by Hg 2. Lead A. Results of recent studies show that children are much more susceptible to the adverse neurological effects of lead than was previously thought B. Sources: i. Seafood (shellfish), Meats, Improperly glazed pottery, Old house paint, Water C. Dietary effects: Lead toxicity is i. Increased with a high fat diet ii. Increased by deficiency of calcium, zinc, iron and protein iii. Partially reduced with antioxidants, vitamins C, E and selenium D. Mechanisms of Toxicity i. The ability to substitute and compete with calcium ion, an essential player in neurotransmission a) Lead can be transported by Ca-ATPase pump, and can enter neurons through VG-calcium channel b) Block and interfere Ca signaling in nervous system ii. Lead inhibits N-methyl-D-aspartate receptor (NMDAR), which is essential for hippocampus-mediated learning and memory a) Amino acids, glutamate, glycine and serine, are NMDAR agonists b) Lead is an NMDAR antagonists and can cause schizophrenia-like symptom iii. Effects: Encephalopathy, Hearing loss, IQ deficits, Hematological effects, Anemia, delayed language acquisition, decreased attention span, learning difficulties E. Lead Poisoning in History i. Beethoven – high levels of lead most likely led to his deafness Lecture 3: Endocrine Disruptors 1. Endocrine System A. Collection of cells, glands, and tissues of an organism that secrete hormones directly into the bloodstream to control the organisms' physiological and behavioral activities B. Endocrine system regulates many aspects of mammalian physiology, including development, growth, metabolism, mood, behaviors, and many other tissue functions C. Endocrinology: the study of the endocrine system; a branch of the wider field of internal medicine. 2. Hormones A. Released by the secreting cell, bind to the receptor of the target cell B. Types of Hormones i. Proteins and Peptides ii. Lipids (steroids, eicosanoids) à last in the circulation longer than others iii. Amino acid derived (thyronines, neurotransmitters, tryptophan) iv. Gases (NO, CO) C. Water soluble: peptide hormones, insulin, growth hormone, catecholamines i. act through membrane receptors D. Fat soluble: steroid hormones, estrogens, androgens, glucocorticoids i. act through nuclear receptors, which are transcription factors proteins (can directly affect gene expression) 3. Homeostasis A. The tendency of an organism or cell to regulate its internal environment and maintain equilibrium, usually by a system of feedback controls, so as to stabilize health and functioning B. Example Hypothalamus releases GnRH à stimulates the anterior pituitary to release LH and FSH à stimulate testes in males to release testosterone/ ovaries in females to release estrogen and progesterone à testosterone, estrogen and progesterone inhibit LH, FSH, and GnRH release (negative feedback) 4. Endocrine disruptors A. Endocrine disruptors are exogenous chemicals that either mimic or block hormone actions B. Mechanism i. alter hormone levels ii. bind to receptors and block normal hormone binding to receptors iii. alter hormonal responses C. Examples i. Pesticides, Plasticizers, Natural plant metabolites, Pharmaceuticals, Detergents, Chemicals from cooking & burning, Antibiotics, Metals D. Many Endocrine disruptors can potentially affect the fetus, as many of them can cross placental barrier E. Results of Disruptions i. Inability to maintain homeostasis ii. Altered growth & development iii. Altered responses to external stimuli iv. Altered behavior v. Suppressed gametogenesis vi. Elevated gestational losses vii. Embryonic malformation viii. Induced neoplasia or carcinogenesis 5. Diethylstilbestrol (DES) A. What it is i. Synthetic non-steroid estrogen B. Biological Mechanism i. Binding affinity to estrogen receptor α is at least 3-5 fold stronger than physiological estradiol ii. DES was given to pregnant women to reduce the risk of pregnancy complications and miscarriage, but later studies showed that DES increases the risk of miscarriage C. Effects i. vaginal tumor in women exposed in utero ii. skin, liver and lung tumors iii. other reproductive system tumors in the female offspring of exposed women 6. Atrazine A. What it is i. Highly used herbicide for corn and grain B. Biological Mechanism i. Strong inhibitor of photosynthesis ii. Atrazine induces aromatase that converts testosterone to estrogen C. Effects i. Caused hermaphroditic, demasculinized frogs D. Note: Aromatase inhibitors are used to treat breast cancer 7. Polychlorinated biphenyls (PCB) A. What it is i. Synthetic lipophilic, halogenated aromatic compound ii. Widely used in industrial and consumer products before their ban in the late 1970s iii. Used in cutting oils, lubricants, and as electrical insulators B. Biological Mechanism i. Estrogenic or anti-androgenic activity ii. Accumulates in food chains, stored in human adipose tissue iii. Exposure through ingestion of contaminated foods C. Effects i. Affect the hypothalamus-pituitary-thyroid (HPT): reduction in the T4 or TSH response to TRH ii. Certain PCBs can interact with thyroid hormone receptors as partial agonists 8. Organochlorine Insecticides: Dichlorodiphenyltrichloroethane (DDT) A. What it is i. 1873 Synthesis by Paul Muller ii. used in WW II to combat malaria iii. came into wide agricultural and commercial use iv. Usage declined because of insect resistance and growing concerns until its ban B. Effects i. Exposure causes reproductive abnormality 9. Streptozotocin (STZ) A. What it is i. Originally identified as an antibiotic ii. found to be selectively toxic to the pancreatic islet beta cells(secrete insulin) iii. pancreatic islets contain alpha cells (secrete glucagon), beta cells (secrete Insulin) and delta cells (secrete somatostatin) B. Biological Mechanism i. STZ causes DNA damage and kills beta cells (it can only enter the cells through glucose transporter 2, which is only expressed in beta cells) ii. Results in no insulin in the body: diabetes iii. Type 1 diabetes: insulin-dependent; auto-immune, as our own Immune system attack and destroy beta cells, 5% of diabetes iv. Type 2 diabetes: insulin-independent; body still secretes insulin, but insulin cannot exert its function to reduce blood glucose levels. Insulin resistance. 95% of diabetes C. Effects i. High blood glucose causes many complications: cardiovascular, Kidney failure, eye damage ii. STZ causes type 1 diabetes-like symptoms 10.Bisphenol A (BPA) A. What it is i. A synthetic chemical used in bottles, toys, CD/DVDs, cell phones, cans, electronics B. Biological Mechanism i. exert estrogen-like effects (like atrazine) ii. may act as an antagonist for thyroid hormone receptor C. Effects i. BPA could have effects on development, reproduction and behavior Lecture 4: Obesogens 1. Obesogens A. Xenobiotics that can cause obesity B. Mechanism i. increase adipocyte differentiation ii. increase lipogenesis (lipid biosynthesis) iii. decrease lipolysis (lipid breakdown) iv. elevate appetite and satiety v. reduce thermogenesis 2. The Mesengenic Process: differentiation of Mesenchymal Stem Cells (MSC) A. Osteogenesis à bone B. Chondrogenesis à cartilage C. Myogenesis à muscle D. Marrow stroma à marrow E. Tendogenesis/ ligamentogenesis à tendons/ ligaments F. Adipogenesis à adipose G. Other à connective 3. Peroxisome proliferator activated receptor γ (PPARγ) A. A master regulator for adipocyte differentiation B. A nuclear receptor whose physiological ligands (hormones) are still unclear C. Note: nuclear receptors are usually transcription factors that affect the expression of specific genes. They also include estrogen, androgen, thyroid hormone and glucocorticoid receptors. 4. Organotins A. A class of compounds used as a stabilizer for PVC (polyvinyl chloride) and as industrial biocides B. Activate PPARγ and promote adipocyte differentiation i. tributyltin [TBT], triphenyltin, and dibutyltin C. Tributyltin: endocrine disruptor, inhibits aromatase activity i. Results in an increase of androgens (male steroid hormones) and masculinization of females 5. Thiazolidinediones (TZD) A. A class of synthetic PPARγ ligands that are used as antidiabetic agents (Avendia, Actos) i. Avendia: shown to increase the incident of heart attack ii. Actos: linked to an increase risk of bladder cancer B. TZD also causes osteoporosis (PPARγ inhibits bone differentiation) 6. Polychlorinated biphenyls (PCB) A. Can affect the hypothalamus-pituitary-thyroid (HPT) axis at several levels i. reduction in the T4 or TSH response to TRH B. Can interact with thyroid hormone receptors as partial agonists 7. Other Obesogens A. Bisphenol A (BPA) and DES: estrogens positively affect adipocyte differentiation


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