Download Environmental Toxicology

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
Secobarbital
Thiopental
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
http://www.blobs.org/science/enzyme/imgs/active2.gif
• 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 2phosphoglycerate  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)
OH
– 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)
• 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
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–
–
–
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
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–
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–
–
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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
http://www.blobs.org/science/metabolism/atp/hydrolysis/option2.gif
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
• Glutathione (GSH)
– Conjugated w/ tripeptide,
then further metabolized
– Tripeptide = glutamic
acid—cysteine—glycine
• Cys has –SH to which
xenobiotic binds
– Further metab 
mercapturic acid of
xenobiotic
– Fig. 10.4
– GSH transferase
• Several
• Specific for diff types chem’s
– Glutathione alkyl transferases, epoxide transferases
– May enhance toxicity
• Final metabolites may bind DNA
• Final metabolites may be converted to reactive
thiols, bind prot’s/enz’s
• Sulfation
– Conjugated w/ adenosine-3’-phosphate-5’phosphosulfate (PAPS)
– Sulfotransferases
– Common substrates: phenols, alcohols,
arylamines
– Prod’s completely ionized
• Very water soluble
Modifiers of Biotransformation
• Diet
– Vitamins, minerals act as coenzymes
• Impt to enz function
• If missing, decr’d metabolism
– Proteins broken down  amino acids
• Used to make more proteins
– Food deprivation  changed metab/abs’n
toxicants
• Hepatic injury
– Liver has many biotransforming enzymes
– Injury  decr’d metab
– Diseases
• Viral infection (hepatitis)
• Jaundice
• Cirrhosis
• Bioactivation
– Metab  more reactive agent
– Often react w/ nucleophilic sites
• Electron-rich
• Seek +-charged compounds
• -SH, -NH2, -OH
• Found on prot’s, nucleic acids
Two or More Toxic Substances
• Synergism
– Total effect greater than sum of individual
effects
• Potentiation
– Inactive substance enhances activity of active
substance
• Antagonism
– Active substance decreases activity of another
active substance