BIOL354 – Environmental Toxicology I Spring 2012
Lecture 14 – Biochemical and Physiological Effects of Chemicals – Part II Organic Pollutants
- Organics: Complex molecules compare to inorganics, more specific interactions & more mechanisms.
Polycyclic Aromatic Hydrocarbons (PAHs) (Fused Benzene Rings)
- Low water solubility, lipophillic (Membrane accumulation).
- Innate form is relatively unreactive/stable, are pro-carcinogens & causes narcosis only @ high s.
- Can be metabolized & are photoactive (absorbs UV radiation ↑ toxicity), do not magnify.
o E.g. Cigarette, nicotine do not cause cancer but addiction; the most stable PAH - Benzo(a)pyrene is
formed during combustion & it is carcinogenic.
Not direct cause & effect but Benzo(a)pyrene is one of the major carcinogens in cigarettes
(correlations only, not proof – tests are too expensive to conduct)
- oxyPAHs/PAH quinones (Oxidized aromatic compounds): Highly reactive, very toxic @ low s, cytotoxic,
genotoxic & mutagenic (carcinogenic).
- 3 Mechanisms to Activate PAHs:
o Photochemical Activation
PAHs within the organism absorbs UV radiation as exposed to light (Photosensitization)
Pre exposure of PAHs (In or out of the cell) to UV → Photomodification/Photooxidation of
PAHs → Production of oxyPAHs
Mechanisms of Photo-induced Toxicity
PAH ground state: singlet PAHs (↑↓e spin is -0.5 + 0.5 = 0)
1PAH*: Activated as it absorbs a photon (hν) → Excited & Singlet state, then PAH* →
3PAH* (↑↑, change in e spin direction)
Oxygen ground state: triplicate O (2↑e spin is 0.5 + 0.5 = 1), not reactive with
singlet state biomolecules.
Photomodification/Photooxidation: PAH* reacts with O to form oxyPAHs
3 3 1 2
Photosensitization: PAH* transfers energy to O → O2 2
o 1O 2excited & singlet) reacts w/ singlet state biomolecules → Tissue damage
Photomodification (oxyPAHs Production): PAHs can be inside or outside of the organism.
E.g. Anthroquinone → 1, 2-dihydroxy-anthroquinone (Inhibits photosynthesis &
Photosensitization ( O 2roduction): PAHs must be in the organism (transparent organisms
are most sensitive).
o Biochemical Activation
Enzymatic transformation of PAHs (to minimize PAH accumulation within membranes)
General Route: Phase I Hydroxylation → Phase II Conjugation (Glutathione-attachment or
glycosylation) → Excretion
Mechanisms of Enzyme-induced Toxicity (↑ PAH solubility for excretion)
99% PAHs Hydroxylated by Cytochrome P450 system or detoxified by Epoxide
Hydroxylase → Glycosylation & Glutathionation → Excretion
1% PAHs escapes glutathionation & glycosylation → carcinogenic (e.g. Diol epoxides)
o Endocrine Disruption (Subset of Biochemical Activation)
Post-metabolism, some oxyPAHs can mimic existing hormones
PAH induced Cytochrome P450 system hydroxylates PAH but can also disrupt the hormone
system of the organism by degrading steroid hormones.
- PAHs & Liver Carcinogenesis in Fish Vignette
o High MW (4-6 Benzene Rings) PAHs are highly mutagenic; they do not bio-magnify up the food chain,
but are activated through photochemical or biochemical pathways (@ liver).
o Excretion is not 100%, some oxyPAH attacks hepatocyte DNA. BIOL354 – Environmental Toxicology I Spring 2012
E.g. Hepatocellular Carcinoma rate ↑ in fishes found Industrialized Regions.
Histopathology (Microscopic examination of tissues) is the End-Point.
E.g. Hepatocellular Carcinoma rate ↑ in Fishes (mummichog) from creosote contaminated
sites (PAH wood preservatives) on the Eastern Seaboard.
- Positive Effects of PAHs: Induce Cytochrome P450 expression
Polychlorinatd Biphenyls (PCBs)
- Not very photoactive & are harder to metabolize than PAHs
o Not manufactured anymore, they must be removed if produced as a by-product
- Highly lipophilic (Persistent in sediments - Membrane accumulation)
- 209 possible congeners/forms (Planer or Eclipsed depends on Cl position & # – Steric Hindrance)
o Eclipsed congeners are more toxic due to higher #s of Cls
- Short Term Acute Toxicity is NOT LIKELY
- Biochemical Activation
o General Route: Uptake → Blood → Liver Metabolism → Excretion
o PCBs hydroxylated by Cytochrome P450 System
Hydroxylation require PCB to have 2 adjacent Cs bonded with H instead of Cl
The greater the # of Cls a PCB has, the harder they are to metabolize
If PCB is not metabolized, they persist in the organism → PCB bioaccumulation & Cl
displacement of DNA bases → Narcosis & Mutations
- Endocrine Disruption
o Activated PCBs can mimic existing hormones & the induced Cytochrome P450 System can disrupt the
natural hormone system of the organism.
E.g. Pophyria: ↑ Aminolevulenic A