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Trail:
Ultra Violet
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 Scientific
papers - Ultra Violet - page 7
UV-Mn INTERACTIONS AND THEIR PUTATIVE INVOLVEMENT IN THE INITIATION OF
TSE PATHOGENESIS
UV photon excitation of Mn could influence biological systems via two
avenues of interaction: either as a UVmediated in situ. photoexcitation
of 'endogenous' Mn in the retina/skin chromophores, or as a
photoexcitation of an 'exogenous'airbom source of Mn particulate which
is directly absorbed into the CNS as a short-lived highly reactive
species via the nasal-olfactory route (36) or via the lungs. Metals such
as titanium, nickel, aluminium, manganese and chlorine (7,116) absorb UV
radiation and subsequently adopt a short-lived excited state which can
readily interact with molecules in biological systems (113,114); thereby
energizing these molecules so that they can generate chain reactions of
hpid peroxidation of membranes with formation of hydroxyl radicals,
increased intracellular Ca uptake (113), etc. whereupon long-term
irreversible damage to proteins, lipids and membranes ensues.
An example of this toxic scenario is well illustrated by the severe
health problems encountered by those who have chronically inhaled
airborne metals that have been energized into excited states by the UV
emitted from the arcs of precision welders working with certain types of
metallic medium (116) - such as manganese steel (35). Another toxic
occupational scenario involves the use of UV as an ink-drying catalyst
in photocopiers/printers, etc., particularly those utilizing inks
containing an Mn additive for its rapid hardening/drying property (44).
The initial contact between 'energized' Mn and external biological
membranes could cause a disruption of the successful incorporation of Mn
into Mn-dependent enzyme systems. For successful binding hinges on the
availability of the correct Mn species that is complementary to the
specificity of the enzyme's active site (9,144). In this respect, once a
'UV-hyperexcited' Mn species is inhaled and makes contact with key Mn-dependent
SOD enzyme systems in the lung alveoli, the redox status of this Mn-dependent
active site could be critically disturbed; resulting in a greatly
diminished activity of Mn SOD in these regions (9). Given that Mn SOD is
the radical scavenger enzyme implicated in neutralizing the oxidizing
effects of airborne contaminants such as ozone (7) - prevalent in high
UV areas - loss of activity would lead to a collapse in the body's first
line of defence against these airborne oxidizing agents.
Likewise, UV-hyperexcited Mn could impair the pathway of Mn heme
assembly (78) by disrupting the assembly of the final protoporphyrinogen
ix-heme product at the end of the Heme biosynthetic pathway where Mn is
inserted into the protoporphyrinogen 1X ring inside the mitochondria
(89, p. 1016). This bears major relevance to TSE pathogenesis in that
porphyrin 1X and phthalocyanines have been shown to protect PrP cells
against formation of the protease-resistant PrP isoform (83) associated
with all TSEs. Thus, once Mn porphyrin assembly is disrupted, protection
against rogue prion formation is lost.
Porphyrins could be inhibiting rogue prion formation (83) (e.g. blocking
the transformation of Mn2+PrP into Mn3+PrP) by harnessing their capacity
to scavenge free electrons onto the 'acceptor' metals within their
pyrole rings, or by scavenging excesses of free Mn/other transition
metals within the cell by incorporating them into their pyrole rings
during the final stages of porphyrin assembly in mitochondria - thereby
serving as an oxidative sink and a potentially useful pharmaceutical for
TSEs.
CONCLUSION
This PrP-porphyrin link (83) suggests that normal PrPc may well perform
some associative functional role with melanin/porphyrin chromophores by
acting as a 'photocitooxidative sink'; where Mn melanins can donate
their photoinduced free electrons onto PrP-Cu acceptors; both molecules
serving as contiguous links in a relay chain which quenches the radicals
generated by the energy of photoexcitation. In this respect, the Cu
domain of PrPc may perform a protective role by conjugating with
systemic xeno-photosensitiser pollutants, thereby neutralising the
singlet oxygen and chernilunimescence that is generated by the
photoenergization of these molecules (Fig. 4)
It is concluded that TSE pathogenesis is initiated once Mn has
substituted at the vacant Cii domain of PrP (15, 16) in the CNS of
susceptibile mammals who reside in high-Mn/low-Cu environs (4). PrP
subsequently looses its Cu-mediated antioxidant function (6), thereby
imparing PrP's capacity to neutralize singlet oxygen and super-oxide
radicals generated by UV-excited melanin A porphyrin/xeno-photosensitiser
chromophores. Mn 2+ is subsequently oxidized into a potent Mn3+/~+
autooxidizing species and full-blown TSE pathogenesis ensues.
TSE outbreaks are currently escalating across many regions of N. Europe,
presenting a potentially serious public health crisis. The reasons for
these outbreaks cannot be explained by the conventional hypothesis. For
instance, BSE outbreaks have erupted for the first time in Germany,
Spain and Italy, while continuing to increase in European countries
already affected such as France, Ireland and Portugal (128) despite bans
on meat and bone meal inclusions into their cattle feed rations being
implemented back in 1990. A situation has developed where a larger
proportion of these countries' total BSE cases involve cattle that were
born after their respective bans on meat and bone meal.
This disturbing trend - coupled with the recent rapid increase of many
other strains of TSE (scrapie (128, 109), CJD, nvCJD (12 1)) across
European countries - raises the urgent need for govemment-backed
research programmes to reopen truly independent investigations which aim
to unravel the causal riddle of TSEs. Preventative measures and
pharmacological therapies for controlling TSEs can only be effectively
implemented once the original cause of this insidious disease has been
thoroughly comprehended.
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