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Environmental Toxicology. Toxicants in Living Organisms. Ingestion Excretion. Phys/chem properties impt Forms Gases, vapors (evap’d solvents), dusts Liquids (in H 2 O) Solids (dissolved). Ingestion Excretion. Phys/chem properties – cont’d pH, pKa, solubility
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Environmental Toxicology Toxicants in Living Organisms
Ingestion Excretion • Phys/chem properties impt • Forms • Gases, vapors (evap’d solvents), dusts • Liquids (in H2O) • Solids (dissolved)
Ingestion Excretion • Phys/chem properties – cont’d • pH, pKa, solubility • Absorption effected? (ex: pH) • Effects toxicity • Ex: aspirin acidic, but neutral in stomach • Must be soluble in body/cell fluids for abs’n • Lipid solubility also impt • Cell membr mostly lipid
Thiopental Secobarbital
Introduction of Toxicants • Exposure • Concentration, dose • Duration, frequency • Site, route • Figure 5.2 • Variations • Species/strain differences • Genetic/health status • Environmental factors (light, temp, etc.)
Sites of Ingestion • Skin • Mostly liquids, solutes in sol’n, suspensions • Greatest area: epidermal cells • blood, lymph body • Blood flow impt • Penetration depends on • Phys/chem properties of toxicant • Skin penetrability • In gen’l nonpolar agents enter
Sites of Ingestion – cont’d • Lungs • Inhale gases, very fine solids/liquids • Major function – gas exch between blood/air
Lungs – cont’d • Alveoli • Thin tissue • Susceptible to absorption gases other than O2 • Toxicants directly blood • Rel large concentrations • Itself susceptible • Particles retained on cilia irritation
Sites of Ingestion-- cont’d • Gastrointestinal (GI) • Major route for solids • Tube: mouth anus • Open to environment • Designed to metabolize, absorb nutrients • Stomach • Low pH promotes abs’n some compounds
GI – cont’d • Small intestine • Absorption • Enterohepatic circulation • Intestine blood liver bile gi blood • Liver • “Screening organ”
Toxicant Storage • Fat • Lipophilic compounds • Many pesticides • Bone • Compounds that bind CaPO4 • Includes small ions
In Cells: Sites of Toxicity • Nucleus • Contains chromosomes (DNA + proteins) • Genes code for partic proteins • DNA dbl helix w/ precise structure, bonds, etc • Proper base pairing • H bonds between bases
Nucleus – cont’d • Transcription • Many steps, proteins nec • DNA mRNA • Translation • Many steps, proteins nec • mRNA protein
Nucleus – cont’d • Toxicants may • Physically disrupt DNA helix • Disrupt repl’n process • Decr’d # new cells • Chem’ly alter bases • Improper base pairing • Mutations • ~ 500 diseases w/ 1 aa change • Often due to defect in genetic code
Major Sites of Toxicants in Cells – cont’d • Enzymes • Proteins that catalyze cellular rxns • Proteins have partic structures • Based on aa’s that make them up • Can be disrupted by cell phys/chem changes
Enzymes – cont’d • Active site • Region holds substrate(s) by multiple weak chem. interactions • Atoms of aa side chains participate in rxn w/ substrate(s) • Rxn catalyzed by lowering energy nec for rxn to take place • Common mech of toxicants is destruction of enz’s, or disruption of their catalytic ability
Enzymes – cont’d • Toxicants may: • Bind covalently at enz active site or other site on enzyme • Compete for enz active site • Unravel enz folding
Enzymes (cont’d) • Toxicants may (cont’d): • Inactivate impt cofactor (inorganic ion nec for enz activity) • Form complex w/ cofactor • Book ex: enolase catalyzes 2-phosphoglycerate phosphoenolpyruvate; req’s Mg+2 • Presence of F Mg-F-PO4 complex inact’n enz • Compete with cofactor • Book ex: Cd replaces Zn
Major Sites of Toxicants in Cells – cont’d • Metabolic Processes • Mitochondria impt • Respiration – aerobic (O2) • Also, anaerobic • Anabolism/catabolism
Metabolic Processes – cont’d • Redox reactions • Shift electrons (1 mol loses e- as [H-] or [H+ + e-]; another gains) • Impt to ATP synth (cell energy) • Toxicants may • Alter enz’s impt to metab improper metabolite • Use metabolic enz’s for toxicant metab improper metabolite
Major Sites of Toxicants in Cells – cont’d • Cell Membrane • Encloses cell • Mostly lipid • Receptor proteins • Lipophilic substances enter • Specific • Cell biochem rxns depend on these
Cell Membrane – cont’d • Toxicants may • Damage lipid bilayer • Damage receptors or shift their structures • Oxidize lipids • Smooth Endoplasmic Reticulum • Contains enzymes involved in metabolism of toxicants
Toxicant Metabolism • Chem nature of toxicants • Extremes of acidity/basicity/ability to add or remove H2O • Corrosive, caustic compounds • Irritants • Very reactive toward mol’s in tissues
Chem nature of toxicants (cont’d) • Highly reactive substances • Bonds, functional groups easily react w/ biomolecules damage • Ex: allyl alcohol vs propanol • Ex: peroxides • Heavy metals • Many react w/ proteins (so enzymes) • May bind –SH grp (cysteine) OH
Chem nature of toxicants (cont’d) • Compounds that bind impt proteins • Reversibly or irreversibly • Ex: CO irreversibly binds Hb • Lipid-soluble compounds • Traverse lipid bilayer • Enter cells easily
Metabolism – cont’d • Ingested toxicant may be • Abs’d as parent • Metab’d first, then abs’d • Stored • Excreted • In general, acted on by metabolic enz’s • Mistaken for food • “Biotransformation” • BUT nonenzymatic biotransformations also • Figure 10.2 – good summary
Dependent on phys/chem properties of xenobiotic • Highly polarized/ionized • Don’t enter cells • Rapidly excr’d • Little harm • Volatile • Expelled quickly from lungs • Little harm • Nonpolar (lipophilic) • Less soluble in aqueous body fluids • Attracted to body lipids • Can accumulate in tissues, fat
Sites of Biotransformation • Metabolic enz’s in tissues • Mostly sites of xenobiotic entry • Skin, lung, gut wall • Incr’d levels metab enz’s • Liver significant • Many types of metabolizing enzymes • “Screening organ” • Sees xenobiotics from g.i. • Enterohepatic circulation • Cycles compounds back to liver
Toxification/Detoxification • Metab detox’d xenobiotic more easily excr’d • Metab tox’d xenobiotic more harmful to cells, body • Ex: polycyclic aromatic hydroxcarbons epoxidized reactive cmpd
Phase I Rxns • Introduce reactive, polar functional grps onto lipophilic mol’s • Modify funct’l grps more hydrophilic • Xenobiotic that looks much diff than parent • Product more easily excr’d OR • Product w/ correct chem. structure to undergo Phase II metab
If not metab’d, lipophilic xenobiotics enter cells or bind serum prot’s & dist’d • Product of Phase I rxns = metabolite more water soluble than parent • More easily excr’d • BUT may be more reactive to cell molecules
Redox Review • Reduction/oxidation rxns • Oxidation = loss electrons • Addition O to structure • Ex: epoxidation • Loss H- (H:) • So ox’d cmpds have fewer H’s or more O’s
Reduction = gain electron • Common: gain H- • So red’d cmpds have more H’s • Ex: coenzymes (NAD+ NADH)
Metabolic Oxidations • Type of Phase I rxn • Frequently by enz’s introducing O • From O2 in body • Mixed Function Oxidases (mfo’s) • Substr + O2 Prod-OH + H2O • Ex: Cytochromes P450
Impt for endogenous mol’s or nutrients • “Microsomal” • Contained in membr’s of organelles • Sep’d by centrifugation
Key enz’s = Cytochromes P450 • Contain heme + Fe + reductase assoc’d • Flavin, NAD coenzymes • Bind O2, add/receive electrons • Liver highest concent in mammals • BUT also other tissues • Table 3.1 • Not all oxidations are microsomal • Ex: Dehydrogenases oxidize –OH • Fig. 10.3
Metabolic Oxidation Rxns of Carbon • Add –OH grps to C’s of HC’s • Add –O- between 2 C’s w/ multiple bond • If unstable get rearrangement • Epoxide form’n more toxic metabolite • Electron rich • Strained ring structure
Metabolic Oxidation Rxns of Noncarbon Elements • N, O, S • Add’n O to N,S • Dehydrohalogenation (nonmicrosomal) • H cleavage near O • Add O
Metabolic Reductions • Gen’ly by reductase enz’s • Liver, kidney, lung, others • Intestinal flora enz’s work on S • Reductive dehalogenation
Hydrolysis (not a redox rxn) • Add H2O across C-C bond 2 prod’s • Ex: epoxide hydratase • Esters, amides • Impt functional grps hydrolyzed • Found in many pesticides • Esterases, amidases • Found in liver • May detoxify or increase toxicity
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Phase II Reactions • Conjugating • Xenobiotic or metabolite of xenobiotic bound to endogenous cmpd • Endogenous cmpd chem’ly activated yields energy for rxn • Xenobiotic funct’l grp = “chemical handle” to which endogenous cmpd is bound
Phase II Reactions • Increases excr’n • Funct’l grp may have been formed by Phase I rxn • Prod more aqueous soluble • Prod less lipid soluble • Prod gen’ly less toxic
Phase II Reactions • Glucuronides • Conjugated w/ uridine diphosphate glucuronic acid (UDPGA) • Glucuronyl transferase • Prod’s classified by funct’l grp element to which glucuronide bound