Environmental Toxicology

1
Environmental Toxicology

• Toxicants in Living Organisms

2
Ingestion ? Excretion

• Phys/chem properties impt
• Forms
• Gases, vapors (evapd solvents), dusts
• Liquids (in H2O)
• Solids (dissolved)

3
Ingestion ? Excretion

• Phys/chem properties contd
• pH, pKa, solubility
• Absorption effected? (ex pH)
• Effects toxicity
• Ex aspirin acidic, but neutral in stomach
• Must be soluble in body/cell fluids for absn
• Lipid solubility also impt
• Cell membr mostly lipid

4
Thiopental
Secobarbital
5
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.)

6
(No Transcript)
7
Sites of Ingestion

• Skin
• Mostly liquids, solutes in soln, suspensions
• Greatest area epidermal cells
• ? blood, lymph ? body
• Blood flow impt
• Penetration depends on
• Phys/chem properties of toxicant
• Skin penetrability
• In genl nonpolar agents enter

8
Sites of Ingestion contd

• Lungs
• Inhale gases, very fine solids/liquids
• Major function gas exch between blood/air

9

• Lungs contd
• Alveoli
• Thin tissue
• Susceptible to absorption gases other than O2
• Toxicants directly ? blood
• Rel large concentrations
• Itself susceptible
• Particles retained on cilia ? irritation

10
Sites of Ingestion-- contd

• Gastrointestinal (GI)
• Major route for solids
• Tube mouth ? anus
• Open to environment
• Designed to metabolize, absorb nutrients
• Stomach
• Low pH promotes absn some compounds

11
(No Transcript)
12

• GI contd
• Small intestine
• Absorption
• Enterohepatic circulation
• Intestine ? blood ?
• liver ? bile ? gi ? blood
• Liver
• Screening organ

13
Toxicant Storage

• Fat
• Lipophilic compounds
• Many pesticides
• Bone
• Compounds that bind CaPO4
• Includes small ions

14
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

15

• Nucleus contd
• Transcription
• Many steps, proteins nec
• DNA ? mRNA
• Translation
• Many steps, proteins nec
• mRNA ? protein

16

• Nucleus contd
• Toxicants may
• Physically disrupt DNA helix
• Disrupt repln process
• Decrd new cells
• Chemly alter bases
• Improper base pairing
• Mutations
• 500 diseases w/ 1 aa change
• Often due to defect in genetic code

17
Major Sites of Toxicants in Cells contd

• Enzymes
• Proteins that catalyze cellular rxns
• Proteins have partic structures
• Based on aas that make them up
• Can be disrupted by cell phys/chem changes

18

• Enzymes contd
• 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 enzs,
  or disruption of their catalytic ability

19
http//www.blobs.org/science/enzyme/imgs/active2.g
if
20

• Enzymes contd
• Toxicants may
• Bind covalently at enz active site or other site
  on enzyme
• Compete for enz active site
• Unravel enz folding

21

• Enzymes (contd)
• Toxicants may (contd)
• Inactivate impt cofactor (inorganic ion nec for
  enz activity)
• Form complex w/ cofactor
• Book ex enolase catalyzes 2-phosphoglycerate ?
  phosphoenolpyruvate reqs Mg2
• Presence of F ? Mg-F-PO4 complex ? inactn enz
• Compete with cofactor
• Book ex Cd replaces Zn

22
Major Sites of Toxicants in Cells contd

• Metabolic Processes
• Mitochondria impt
• Respiration aerobic (O2)
• Also, anaerobic
• Anabolism/catabolism

23

• Metabolic Processes contd
• Redox reactions
• Shift electrons (1 mol loses e- as H- or H
  e- another gains)
• Impt to ATP synth (cell energy)
• Toxicants may
• Alter enzs impt to metab ? improper metabolite
• Use metabolic enzs for toxicant metab ? improper
  metabolite

24
Major Sites of Toxicants in Cells contd

• Cell Membrane
• Encloses cell
• Mostly lipid
• Receptor proteins
• Lipophilic substances enter
• Specific
• Cell biochem rxns depend on these

25

• Cell Membrane contd
• Toxicants may
• Damage lipid bilayer
• Damage receptors or shift their structures
• Oxidize lipids
• Smooth Endoplasmic Reticulum
• Contains enzymes involved in metabolism of
  toxicants

26
Toxicant Metabolism

• Chem nature of toxicants
• Extremes of acidity/basicity/ability to add or
  remove H2O
• Corrosive, caustic compounds
• Irritants
• Very reactive toward mols in tissues

27

• Chem nature of toxicants (contd)
• 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
28

• Chem nature of toxicants (contd)
• Compounds that bind impt proteins
• Reversibly or irreversibly
• Ex CO irreversibly binds Hb
• Lipid-soluble compounds
• Traverse lipid bilayer
• Enter cells easily

29
Metabolism contd

• Ingested toxicant may be
• Absd as parent
• Metabd first, then absd
• Stored
• Excreted
• In general, acted on by metabolic enzs
• Mistaken for food
• Biotransformation
• BUT nonenzymatic biotransformations also
• Figure 10.2 good summary

30
(No Transcript)
31

• Dependent on phys/chem properties of xenobiotic
• Highly polarized/ionized
• Dont enter cells
• Rapidly excrd
• 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

32
Sites of Biotransformation

• Metabolic enzs in tissues
• Mostly sites of xenobiotic entry
• Skin, lung, gut wall
• Incrd levels metab enzs
• Liver significant
• Many types of metabolizing enzymes
• Screening organ
• Sees xenobiotics from g.i.
• Enterohepatic circulation
• Cycles compounds back to liver

33
Toxification/Detoxification

• Metab ? detoxd xenobiotic ? more easily excrd
• Metab ? toxd xenobiotic ? more harmful to cells,
  body
• Ex polycyclic aromatic hydroxcarbons epoxidized
  ? reactive cmpd

34
Phase I Rxns

• Introduce reactive, polar functional grps onto
  lipophilic mols
• Modify functl grps ? more hydrophilic
• ? Xenobiotic that looks much diff than parent
• ? Product more easily excrd OR
• ? Product w/ correct chem. structure to undergo
  Phase II metab

35

• If not metabd, lipophilic xenobiotics enter
  cells or bind serum prots distd
• Product of Phase I rxns metabolite more water
  soluble than parent
• More easily excrd
• BUT may be more reactive to cell molecules

36
Redox Review

• Reduction/oxidation rxns
• Oxidation loss electrons
• Addition O to structure
• Ex epoxidation
• Loss H- (H)
• So oxd cmpds have fewer Hs or more Os

37

• Reduction gain electron
• Common gain H-
• So redd cmpds have more Hs
• Ex coenzymes (NAD ? NADH)

38
(No Transcript)
39
Metabolic Oxidations

• Type of Phase I rxn
• Frequently by enzs introducing O
• From O2 in body
• Mixed Function Oxidases (mfos)
• Substr O2 ? Prod-OH H2O
• Ex Cytochromes P450

40

• Impt for endogenous mols or nutrients
• Microsomal
• Contained in membrs of organelles
• Sepd by centrifugation

41

• Key enzs Cytochromes P450
• Contain heme Fe reductase assocd
• 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

42
(No Transcript)
43
Metabolic Oxidation Rxns of Carbon

• Add OH grps to Cs of HCs
• Add O- between 2 Cs w/ multiple bond
• If unstable get rearrangement
• Epoxide formn ? more toxic metabolite
• Electron rich
• Strained ring structure

44
Metabolic Oxidation Rxns of Noncarbon Elements

• N, O, S
• Addn O to N,S
• Dehydrohalogenation (nonmicrosomal)
• H cleavage near O
• Add O

45
Metabolic Reductions

• Genly by reductase enzs
• Liver, kidney, lung, others
• Intestinal flora enzs work on S
• Reductive dehalogenation

46
Hydrolysis (not a redox rxn)

• Add H2O across C-C bond ? 2 prods
• Ex epoxide hydratase
• Esters, amides
• Impt functional grps hydrolyzed
• Found in many pesticides
• Esterases, amidases
• Found in liver
• May detoxify or increase toxicity

47
http//www.blobs.org/science/metabolism/atp/hydrol
ysis/option2.gif
48
Phase II Reactions

• Conjugating
• Xenobiotic or metabolite of xenobiotic bound to
  endogenous cmpd
• Endogenous cmpd chemly activated yields energy
  for rxn
• Xenobiotic functl grp chemical handle to
  which endogenous cmpd is bound

49
Phase II Reactions

• Increases excrn
• Functl grp may have been formed by Phase I rxn
• Prod more aqueous soluble
• Prod less lipid soluble
• Prod genly less toxic

50
Phase II Reactions

• Glucuronides
• Conjugated w/ uridine diphosphate glucuronic acid
  (UDPGA)
• Glucuronyl transferase
• Prods classified by functl grp element to
  which glucuronide bound

51

• Glutathione (GSH)
• Conjugated w/ tripeptide, then further
  metabolized
• Tripeptide glutamic acidcysteineglycine
• Cys has SH to which xenobiotic binds
• Further metab ? mercapturic acid of xenobiotic
• Fig. 10.4

52

• GSH transferase
• Several
• Specific for diff types chems
• Glutathione alkyl transferases, epoxide
  transferases
• May enhance toxicity
• Final metabolites may bind DNA
• Final metabolites may be converted to reactive
  thiols, bind prots/enzs

53

• Sulfation
• Conjugated w/ adenosine-3-phosphate-5-phosphosul
  fate (PAPS)
• Sulfotransferases
• Common substrates phenols, alcohols, arylamines
• Prods completely ionized
• Very water soluble

54
(No Transcript)
55
Modifiers of Biotransformation

• Diet
• Vitamins, minerals act as coenzymes
• Impt to enz function
• If missing, decrd metabolism
• Proteins broken down ? amino acids
• Used to make more proteins
• Food deprivation ? changed metab/absn toxicants

56

• Hepatic injury
• Liver has many biotransforming enzymes
• Injury ? decrd metab
• Diseases
• Viral infection (hepatitis)
• Jaundice
• Cirrhosis

57

• Bioactivation
• Metab ? more reactive agent
• Often react w/ nucleophilic sites
• Electron-rich
• Seek -charged compounds
• -SH, -NH2, -OH
• Found on prots, nucleic acids

58
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