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Heme Pathway. |
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Enzymes
# 1, 6, 7, & 8 are located in the mitochondrion — the other
enzymes are located in the cytosol. Enzyme # 3, porphobilinogen deaminase,
is the biochemical lesion in AIP, wherein the concentration is about 50%
of normal |
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* It
is the first enzyme in the pathway, ALA synthetase, that
is normally rate-limiting. Therein lies the major control
feature because the end product of the pathway, heme, causes both
a repression and an inhibition of ALA synthetase. This is indicated
in figure 2 by a dotted arrow impacting on enzyme # 1. |
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* Because
porphobilinogen deaminase is not rate-limiting to the overall pathway,
50% of normal is sufficient for unstressed AIP patients. This explains
the lack of symptoms for latent AIP patients and the intervening periods
of normalcy for patients who have experienced periods of sickness. When
the heme concentration of liver cells is depleted, the effective amount
of ALA synthetase may be increased over ten-fold. Under those
circumstances the "partial road block" at enzyme number three
is felt by AIP patients, and toxic levels of the preceding compounds are
produced. |
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* Ingested
compounds that are metabolized via cytochrome P450's in the liver deplete
the heme pool and induce the synthesis of ALA synthetase. These include
alcohol, many drugs, and many xenobiotics. The van Gogh terpenes (camphor,
thujone and pinene)3 can be added to that growing list. |
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*
An hydraulic model of the control mechanism is offered
to assist the non-chemical reader.
Click on image to enlarge.
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| Hydraulic
model for control of heme pathway |
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* The
diagram on the left of figure 3 portrays each intermediate compound (a,
b, c ... heme) as a solution in a cylinder being acted upon by an enzyme
(exit tube) as it passes on to the next vessel. The AIP patient has about
half the normal amount of the third enzyme (exit partly closed by the
bold arrow). But the overall flow is steady, thanks to regulation of the
first enzyme (the float mechanism senses the level of the metabolic heme
pool). The diagram on the right depicts the consequence of depleting the
heme pool (pulling the plug): the activity of the first enzyme increases
greatly (increased drop-size in the model) and now the partial block at
the third enzyme (in the AIP patient) comes into play. Compounds c and
d accumulate and will "spill-out." In the formal pathway, c
and d are delta-aminolevulinc acid (ALA) and porphobilinogen. |
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* On
the other hand, synthesis of ALA synthetase can be decreased by
high glucose intake, thus helping to explain the ameliorating
effect of a high carbohydrate diet on AIP attacks and the adverse
effect of malnutrition or fasting. |
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* AIP
crises are also treated with therapeutic, intravenous doses of hematin
whose effectiveness is related to artificially increasing the
"heme pool" in the liver. In extreme cases a prophylactic administration
of hematin on a regular basis has been found useful. |
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Biochemical
summary for AIP |
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* The
AIP patient has a vulnerable heme pathway. The neurological
problems associated with medical attacks are a consequence of upsetment
of the heme pathway and the toxic accumulation of two intermediate
compounds, delta-aminolevulinc acid (ALA) and porphobilinogen. |
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Port
wine urine |
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Only
under a crisis does the typical AIP patient excrete large amounts of delta-aminolevulinic
acid and porphobilinogen in the urine. Even then the freshly voided
urine is of normal color, but with time these compounds polymerize
to form porphobilin which imparts a brown or
red pigmentation to aged specimens. |
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* The
final color is influenced by concentration, pH, light, oxygen
and temperature. The propitious availability of a porphyric urine
sample together with the low-tech "windowsill test" can be very
instructive in the diagnosis of AIP. |
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* Urine
which has aged internally due to bladder dysfunction
may already be discolored when released with a catheter, although the
color is sometimes mistaken for urinary tract bleeding. |
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* In
contradistinction to the claim that "port wine urine"
is the faithful telltale sign of AIP, it is worth emphasizing that many
20th century carriers with documented medical attacks have never remarked
upon abnormally colored urine because it was either not saved or not aged.
Dark or red urine is not mentioned in the published van Gogh letters but
this really does no damage to the AIP hypothesis. |
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Main
Index