Robert, For heaven sakes, what exactly is there to feel guilty about?
First of all, it was late last night, I had intended to send another
letter to the list with references, and I am really sorry that this
happened. One letter was suppose to go to the list, and this one
was suppose to go to my father. My apologies... and maybe my letter
wasn't clear, this had nothing to do with alcoholic liver damage,
but it may have something to do with my father's work, that he
was exposed to chemicals that could have injured his liver. What
this paper was about was based on the following. Perhaps you haven't
seen these studies? I just wanted some feedback on the work that is
being done at King's College, London, UK Best, Linda
Neuroscience 1998 Sep;86(2):511-9
Co-localization of P450 enzymes in the rat substantia nigra with
tyrosine
hydroxylase.
Watts PM, Riedl AG, Douek DC, Edwards RJ, Boobis AR, Jenner P, Marsden
CD
Neurodegenerative Disease Research Centre, Biomedical Sciences Division,
.
[Medline record in process]
Susceptibility to develop Parkinson's disease has been linked to
abnormalities of P450 enzyme function. Multiple P450
enzymes are expressed in brain but the relationship of these to
Parkinson's disease is unknown. We have investigated the
expression of P450 enzymes in the rat substantia nigra and their
co-localization in tyrosine hydroxylase-positive neurons and
astrocytes. Immunohistochemistry was performed using anti-peptide
antisera against the following P450 enzymes: CYP1A1,
CYP1A2, CYP2B1/2, CYP2C12, CYP2C13/2C6, CYP2D1, CYP2D4, CYP2E1, CYP3A1,
CYP3A2 and
NADPH-P450 oxidoreductase. Immunoreactivity in nigral cells was found
only for CYP2E1 and CYP2C13/2C6. CYP2E1
immunoreactivity was localized to many midbrain nuclei including the
substantia nigra pars compacta but not the substantia
nigra pars reticulata while immunoreactivity to CYP2C13/2C6 was found in
the substantia nigra pars compacta, substantia
nigra pars reticulata and many other midbrain nuclei. Sections of rat
midbrain double labelled for either CYP2E1 or
CYP2C13/2C6 and tyrosine hydroxylase or glial fibrillary acidic protein
were examined for co-localization by confocal laser
scanning microscopy. CYP2E1 and CYP2C13/2C6 immunoreactivity was found
in tyrosine hydroxylase-positive neurons in
the substantia nigra pars compacta but not in glial cells. CYP2C13/2C6,
but not CYP2E1, was also found in non-glial,
non-tyrosine hydroxylase-expressing cells in the substantia nigra pars
reticulata. Isoniazid induction increased CYP2E1
fluorescence signal intensity from nigral dopaminergic neurons. At least
two P450 enzymes are found in nigral dopamine
containing cells and one, namely CYP2E1, is selectively localized to
this cell population. CYP2E1 is a potent generator of
free radicals which may contribute to nigral pathology in Parkinson's
disease. The expression of CYP2E1 in dopaminergic
neurons in substantia nigra raises the possibility of a causal
association with Parkinson's disease.
PMID: 9881865, UI: 99096192
Mov Disord 1998;13 Suppl 1:24-34
Oxidative mechanisms in nigral cell death in Parkinson's disease.
Jenner P
Neurodegenerative Disease Research Centre, Biomedical Science Division,
London, United Kingdom.
Oxidative stress may contribute to nigral cell death in Parkinson's
disease based on postmortem investigations showing
increased iron levels, decreased levels of reduced glutathione (GSH),
and impaired mitochondrial function. This leads to
oxidative damage because lipid peroxidation is increased in substantia
nigra and there is a widespread increase in protein and
DNA oxidation in the brain in Parkinson's disease. Nitric oxide (NO) may
be one of the free radical species involved in
nigral degeneration. NO is involved in the production of hydroxyl
radicals resulting from MPP+-induced dopamine efflux in
striatum. Mice treated with the neuronal nitric oxide synthase (NOS)
inhibitor 7-nitroindazole show reduced toxicity to
MPTP and knock-out mice lacking neuronal NOS show decreased MPTP
susceptibility. In primates, 7-nitroindazole
inhibits MPTP toxicity but this remains controversial because no
protection is afforded by the nonspecific NOS inhibitor,
L-NAME. Indeed, in Parkinson's disease itself, there is little evidence
for nitric oxide's involvement in nigral pathology. A
susceptibility factor for the development of Parkinson's disease may
involve isoforms of cytochrome P450, some of which
are found in the brain. CYP2EI, which is associated with free radical
production and the formation of endogenous toxins, is
selectively localized in nigral dopamine-containing cells. CYP2E1
metabolizes n-hexane leading to the formation of its
neurotoxic metabolite 2,5-hexanedione which may explain cases of
solvent-induced parkinsonism. Oxidative processes
clearly contribute to the pathology of Parkinson's disease but are
probably secondary to some other primary unidentified
cause, presumably genetic or environmental. Nevertheless, their
involvement may allow therapeutic intervention in the
cascade of events associated with the progression of Parkinson's
disease.
Publication Types:
Review
Review, tutorial
PMID: 9613715, UI: 98273771
