Hydrocarbons: Mechanisms of Cellular Toxicity - PowerPoint PPT Presentation

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Hydrocarbons: Mechanisms of Cellular Toxicity

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Accumulate in fatty tissues, fat stores. Fatty tissue life may be 100 d. Secr'd in milk ... Other prot's impt to cell viability, replication ... – PowerPoint PPT presentation

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Title: Hydrocarbons: Mechanisms of Cellular Toxicity


1
Hydrocarbons Mechanisms of Cellular Toxicity
2
Organohalides Are Lipophilic
  • Less available for excrn
  • Accumulate in fatty tissues, fat stores
  • Fatty tissue ½ life may be gt 100 d
  • Secrd in milk
  • Bioaccumulate in aquatic spp
  • Partition out of water
  • ? Sediments
  • ? Fish fatty tissue

3
  • Organisms may accumulate 3-6x (or more) amt in
    env water

4
Polynuclear Aromatic Hydrocarbons
  • Benzo(a)pyrene, benz(a)anthracene models
  • Metabolized by mixed function oxidases
  • Cytochromes P450
  • ? Reactive diol epoxides
  • Oxd forms in bay region most toxic

5
bay region
6
Halogenated Hydrocarbons May Increase Their Own
Toxicity
  • Work through Ah receptor
  • Induce prodn Cyt P450 enzs
  • ? Oxidized cmpds
  • Ex 7,8-Dihydro-7,8-dihydroxy-benzopyrene 9,10
    epoxide

7
The Ahreceptor binds four classes of substances
Dibenzodioxines (i.e TCDD) A, Dibenzofuranes, B
Biphenyls C and polyaromatic hydrocarbons D. If
such substances reach the receptor E, they
trigger a chemical signal, which will finally
result in toxic phenomena tumor growth, skin
toxicity (i.e. Ah mediated chloracne) F,
immunotoxicity as well as developmental toxicity.
The dioxin receptor belongs to the class of
receptors mediating toxicity, which are
preferentially modelled by QSAR methods.
3r-training.tierversuch.ch/.../dioxin.html
8
  • Hydrocarbon binds Ah receptor in cytosol
  • Complex translocates ? nucleus
  • ? Specific recognition sites on DNA for complex
  • Ah gene locus
  • Now transcrn, transln initiated
  • Specific genes code for AHH
  • Aryl hydrocarbon hydroxylase
  • Phase I enzyme
  • Structural gene for cytosolic receptor

9
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10
Increased Toxicity of Metabolites
  • Now more metabolic (Cyt P450) enzs
  • Catalyze more oxn of parent cmpd
  • Product now more toxic
  • Incrd carcinogenesis
  • May covalently bind DNA
  • ? Mutations, incrd repln

11
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12
PolyChlorinated Biphenyls
  • PCBs
  • 210 poss congeners
  • Chem cmpd closely related to another in
    composition
  • Exerting similar or antagonistic effects
  • Something derived from same source or stock
  • Widespread, persistent
  • In fat tissue of most humans

13
  • Two most potent
  • 3,4,3,4-tetrachloro biphenyl
  • 3,4,5,3,4,5-hexachloro biphenyl

14
Halogen Substitutions
  • Cl is a halogen
  • F, Cl, Br, I
  • Reactive
  • Wants 1 e- to fill outer shell
  • Form ions w/ single negative charge

15
  • In halogenated hydrocarbons, Cl covalently bound
    to C
  • Electronically stable bond
  • Most mols containing Cl man-made
  • ? incrd molecular stability, incrd MW, incrd
    bpt/mpt

16
  • Cl substitutions on biphenyl often balanced
  • When ortho substituted w/ Cl
  • Cl relatively large
  • 2 planar rings cant rotate
  • Rotation hindered by Cls
  • When no Cl, 2 planar rings can rotate
  • About C1, C1 bond

17
PCB Toxicity
  • Low acute toxicity
  • Chronic exposure not understood
  • Probably more harmful
  • Combines w/ receptor
  • Ah (aryl hydrocarbon) receptor
  • PCB ?? PCB-Receptor ? Nucleus ? DNA ? alter
    transcription ? effect on cell

18
Three Modes of Action
  • Bind cell macromols
  • DNA
  • Stacks and sticks to proteins
  • Accumulate in lipid-rich cell components
  • Reversibly bind receptors, enzymes
  • At specific sites
  • Ah receptor has great affinity for TCDD, PCBs
  • Via Cls

19
PCB Biotransformation
  • Bioactivation depends on planarity
  • More toxic (and more similar to dioxin) when
  • Coplanarity of rings
  • Cls at m, p positions
  • Metabd through Phase I and Phase II

20
Phase I Metab
  • Cytochrome P450 monooxygenase common
  • Indirect hydroxylation
  • OH added, then db in ring shifts
  • Epoxidation
  • --O added over db in ring
  • May or may not shift or lose Cl
  • Metab rate depends on , placement Cls
  • More rapid if gt4 Cls and Hs on Cs 4,5

21
Phase II Metab
  • Phase II Reactions
  • Conjugated to glucuronic acid
  • Rapidly excrd
  • Conjugated to GSH
  • ? Mercapturic acid
  • Excrd or reabsd

22
Common Effects of PCBs
  • Note many effects are species-specific
  • Coplanarity of rings, Cls related to potency
  • Chloracne
  • Acneiform eruption w/ exposure
  • Milder than w/ TCDD
  • Probably diff mech

23
  • Epithelial cell changes
  • Hyperplasia Incrd cell w/ incrd cell divn
  • Hypoplasia Decrd cell division ? decrd
    proliferating cells
  • Impt to changes in sev organs
  • Hepatomegaly
  • Gastric mucosal changes
  • ? Ulceration, hemorrhage
  • Species specific
  • May play role in carcinogenesis
  • Hyperplasia incrd cell division may be
    precursor for
  • Cancer unrestrained cell division

24
  • Vit A depletion
  • May be linked to Ah receptor
  • Heme prodn inhibd
  • Get build-up of porphyrins which are toxic
  • Immunosuppression
  • Lymph glands
  • Spleen enlargement
  • Thymus gland atrophy
  • Total serum Igs decline (species specific)
  • Humans IgA, IgM sig depressed
  • Phagocyte , T cell response depressed
  • From Japan, Taiwan PCB poisoning epidemics

25
  • Nervous system disorders
  • Catecholamine levels changed
  • Behavioral, learning dysfunctions
  • Offspring following prenatal exposure
  • Endocrine disruption
  • Next weeks lecture

26
Dioxins
  • Also widespread
  • Also hydrophobic
  • Most toxic
  • 2,3,7,8-tetrachlorodibenzo-p-dioxin

27
  • Supertoxic cmpd
  • Extremely potent
  • Diff isomers differ in toxicity
  • Contaminant of other chlorinated cmpds
  • Induces microsomal enzs
  • May be through Ah receptor

28
  • TCDD binds Ah receptor in cytosol
  • Some spp (even diff strains) have varied amts Ah
    receptor in cytosol
  • More receptor/higher sensitivity to TCDD
  • Complex translocates ? nucleus
  • ? Specific recognition sites on DNA for complex
  • Ah gene locus

29
  • Now transcrn, transln initiated
  • Specific genes code for AHH
  • Aryl hydrocarbon hydroxylase
  • Phase I enzyme
  • Structural gene for cytosolic (Ah) receptor
  • Other prots impt for immune, inflamm responses
    (?)
  • Other prots impt to cell viability, replication

30
http//www.med.ufl.edu/pharm/facdata/Shiveric/imag
es/TCDD.gif
31
Toxicity in Humans Uncertain
  • Incrd cancer mortality?
  • Carcinogenic in rats (_at_ 2 ppb)
  • ? Cancers of liver, resp tract, mouth, others
  • Not reported to be carcinogenic in humans in
    spite of its extremely potent carcinogenicity in
    rats (WHO, 1989)
  • German pesticide workers suffer 39 higher cancer
    mortality rate compared to other Germans.
    (Hanson, David 1991)

32
  • Chloracne
  • Most characteristic lesion in humans
  • Related to Ah receptor
  • Hepatotoxicity at high doses
  • See hyperplasia, enzyme induction, others
  • Immunosuppression
  • T cells most likely target
  • Species specific
  • Reversible
  • Teratogenicity/fetotoxicity
  • Cleft palate/Ah receptor linked in mice?
  • Prenatal exposure ? biochem behavioral changes
    in offspring

33
Some Problems in Assessing Toxicity
  • TCDD, congeners may be by-products of manufacture
    along with PCBs
  • So which is responsible for toxicity?
  • DDT often present in mixtures, animals,
    environment
  • Pesticide, but also manufacturing by-product
  • OR may be in environment previously
  • OR may have been in animal fat from earlier
    exposure

34
  • One toxicant may influence others in mixture
  • Synergism or antagonism
  • Which in a mixture is most toxic?
  • Cant fully assess mechanisms
  • Difficult to assess environmental risk
  • Molecule in largest concent may not be most toxic
  • If one toxicant induces metab of another ????
  • Species specificity impt
  • Fat stores? (ex mink)
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