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http://www.alternativementalhealth.com/articles/pyroluria.htm

 

Our thanks to the following for making this information available to us.

 

DIRECT HEALTHCARE ACCESS II LABORATORY

350 W. KENSINGTON ROAD SUITE 107

MOUNT PROSPECT IL 60056

Tel. 847-222-9546 Fax 847-222-9547

email: dha1825

(We do testing for urinary pyrroles.)

 

 

Pyroluria: Hidden Cause of Schizophrenia, Bipolar, Depression, and

Anxiety Symptoms

by Woody McGinnis, M.D.

Orlando 21 May 2004

 

 

In the late 1950's a team of Canadian researchers lead by Abram Hoffer

encountered an unusal compound in the urine of schizophrenic patients.

The compound produced a lilac-colored (mauve) spot on paper

chromatograms developed with Ehrlich's reagent. The qualitative assay

available at the time revealed the so-called 'Mauve Factor' in about

2/3 of recent-onset schizophrenics, but not in controls. 100% of the

schizophrenic subgroup which recovered on high-dose niacinamide

(vitamin B3) were found to have converted from Mauve-positive to

Mauve-negative. Relapses associated with discontinuation of

niacinamide were associated with reappearance of Mauve.

 

Through the 1960's Hoffer and others published clinical outcomes on

hundreds of schizophrenics and other high-Mauve diagnostic groups,

such as " mentally retarded " and " disturbed " children and criminals. In

the early 1970's an American team lead by Carl Pfeiffer introduced a

relatively simple, quantitative colorimetric assay for urinary Mauve

utilizing kryptopyrrole, which is similar to Mauve, as standard.

Pfeiffer demonstrated suppression of urinary Mauve and commensurate

clinical improvement with high-doses of vitamin B6 and zinc, which

have become the treatment of choice.

 

Originally, Mauve was identified erroneously as kryptopyrrole.

'Kryptopyrrole' is not accurate terminology for Mauve. Technological

advances in the 1970's allowed correct identification of Mauve as

OHHPL (hydroxyhemoppyrrolin-2-one). By synthesis (Irvine), GLC

(Graham), and HPLC/MS (Audhya), biological Mauve is OHHPL. It is a

member of the pyrrole family, and may be correctly referred to as

" urinary pyrrole " . Interchangeable use of 'Mauve' and 'OHHPL' seem

logical and efficient to this writer.

 

This compound is detectable in urine, blood and cerebrospinal fluid.

It is heat- and light-sensitive, and requires ascorbate preservative

if there is any delay in processing. Graham demonstrated that

adjustment to urinary creatinine concentration is not necessary. The

Mauve urine level is a useful predictor of higher vitamin B6 and zinc

requirements, and may be used to help titrate dosage levels in a wide

range of behavioral and somatic problems associated with high

excretion. In Europe, especially, many clinicians use Mauve assay in

the management of strictly somatic health problems.

 

Higher Mauve levels are found in Down syndrome 70%, schizophrenia up

to 70%, autism 50%, ADHD 30%, and alcoholism up to 80%. One mixed

group of general medical patients-arthiritis, chronic fatigue, heart

disease, hypertension, irritable bowel and migraine-had mauve

elevations in 43%. One-third of cancer patients--particularly lung

cancer--are high-Mauve.

 

Certain signs and symptoms are more common in high-mauve patients.

Pfeiffer reported more nail spots, stretch marks, pale skin, knee

pain, constipation, poor dream recall, morning nause, light-sound-odor

intolerance, migraines and upper abdominal pain. To this list Walsh

adds low stress tolerance, anxiety, pessimism, explosive anger and

hyperactivity. Jaffe and Kruesi found more social withdrawal,

emotional lability, loss of appetite and fatiguability. Not all

patients with higher urinary Mauve have all or most of these symptoms.

 

In 1965, O'Reilly documented association of higher urinary Mauve with

stress, and many publications have confirmed this. An unpublished

study by Tapan Audhya in 1992 demonstrated a significant increase in

urinary Mauve in healthy subjects after cold-water stress. Pfeiffer

introduced the practice of giving extra vitamin B6 and

zinc-'stress-doses'-to buffer physical or emotional stress in

high-Mauve patients.

 

Pfeiffer also imprinted the field with the assertion that Mauve

complexes with P5P--the active form of vitamin B6--and zinc, with

resultant deficiency of these two nutrients due to increased urinary

excretion. Existing data are insufficient to support or reject this

proposed mechanism.

 

Our current data, pending publication, do establish a strong negative

correlation between urinary Mauve and zinc status, when Mauve is

measured either by the colorimetric assay or by HPLC/MS. A series of

1148 ADHD patients (Walsh) demonstrated a strong negative correlation

(0.974 significance by F test) between Mauve by colorimetric assay and

plasma zinc concentration. Mauve by colorimetric analysis in a mixed

group of patients (McLaren-Howard) demonstrated a strong negative

correlation with white-cell zinc (correlation coefficient -0.743).

Also in mixed diagnoses, there was a very strong inverse correlation

(coefficient -0.985) between Mauve by HPLC/MS and red-cell zinc

(Audhya). There is sufficient evidence to conclude that Mauve is a

good marker for zinc status.

 

Riordan and Jackson find that vitamin B6 (pyridoxine) levels are not

lower in association with urinary Mauve. Pfeiffer alluded to lower

vitamin B6 function in high-Mauves, as reflected by lower measured

levels of P5P (activated vitamin B6) and EGOT activity. There is no

published data in this area. Suspected functional deficits in

activation of vitamin B6 and / or binding by B6-dependent enzymes will

be discussed later in the context of oxidative stress.

 

OHHPL has not been studied exhaustively, but preliminary data are very

interesting. In 1977, Irvine demonstrated that OHHPL concentration in

urine directly correlated with emotional withdrawal, motor

retardation, blocked affect and severe depression in schizophrenia. He

also demonstrated that intraperitoneal administration of OHHPL

resulted in ptosis, locomotor aberration, and hypothermia in rats. In

1990, Cutler and Graham reported increased backward locomotion and

head-twitching (as with psychotomimetics) in mice after

intraperitoneal OHHPL administration. Graham suggested that the

chemical similarity of OHHPL to kainic acid and pyroglutamate confer

excitotoxic properties. This has not been investigated.

 

That seemingly disparate treatments-niacinamide on one hand, vitamin

B6 and zinc on the other-decrease Mauve and produce concommitant

symptomatic improvement is thought-provoking. In both humans and

animals, an ample body of research demonstrates that emotional,

non-physically painful stress increases oxidative stress, measurable

as actual oxidized biomolecules. The behavioral and somatic disorders

associated with higher urinary Mauve are also associated with higher

markers for oxidative stress. B6 and Zn and B3 are strongly

anti-oxidant, which strengthens the suggestion that Mauve is

associated with oxidative stress.

 

Lower zinc, as found in higher-Mauve states, certainly is associated

with oxidative stress. Zinc is powerfully anti-oxidant, shielding

sulfhydryl groups and protecting lipids from peroxidation. Zinc

induces metallothionein, a very important anti-oxidant protein, and is

a constituent of superoxide dismutase. Levels of vitamin A-a key

antioxidant-are maintained by sufficient zinc. Zinc deficiency results

in lower glutathione, vitamin E, glutathione sulfotransferase (GST),

glutathione peroxidase and superoxide dismutase levels. Reactive

oxygen species and lipid peroxides increase in tissue, membranes and

mitochondria in zinc deficiency.

 

Conceivably, poor zinc retention and higher zinc turnover may be a

manifestation of oxidative stress. It is well-demonstrated that

oxidants release complexed zinc from zinc-binding proteins, including

metallothionen. Thus, it is suspected that the relationship between

oxidative stress and low zinc are reciprocal.

 

Vitamin B6 is strongly anti-oxidant. P5P is required for synthesis of

glutathione, metallothionein, CoQ10 and heme, all of which play very

important anti-oxidant roles. With zinc, P5P is required for glutamic

acid decarboxylase (GAD), sufficient supplies of which block

excitotoxicity which would otherwise increase oxidative stress. P5P

protects vulnerable enzyme lysinyl groups from oxidation, as

specifically in the case of glutathione peroxidase.

 

Even marginal B6 deficiency lowers glutathione peroxidase and

glutathione reductase, promoting mitochondrial decay and raising

measurable lipid peroxide levels. Carbonyl-inhibition of pyridoxal

kinase, which produces P5P, is very strong. It is possible that higher

levels of carbonyls produced by oxidative injury to proteins may exert

an inhibiting effect on B6 activation in states of oxidative stress.

Besides pyridoxal kinase, the whole family of P5P-dependent enzymes

suffer decreased binding in the face of carbonyl inhibition, and

certain key P5P-dependent enzymes such as GAD are impaired by oxidants

generally.

 

Thus, there exist numerous ways by which impaired vitamin B6 function

and oxidative stress reciprocate. Hydroxyl radical and superoxide even

attack vitamin B6 vitamers directly. High doses of B6 may compensate

oxidatively-impaired enzyme and co-enzyme function in high-Mauve

subjects.

 

B3 is strongly anti-oxidant. It is needed for the NADPH which is

required for reduction of glutathione. B3 is a potent free-radical

quencher, protecting both lipids and proteins from oxidation. It

blocks nitric-oxide associated neurotoxicity. Normally, the body

maintains relatively high vitamin B3 tissue levels, which can serve a

very important anti-oxidant function. At usual physiologic

concentrations, B3 exceeds the anti-oxidant effects of ascorbate in

some studies. Vitamin B3 antagonists increase lipoxidation. Low

vitamin B3 decreases metallothionein and increases apoptosis in brain

cells. In experimental mitochondrial toxicity, B3 is neuroprotective.

 

Oxidative stress, poor energetics, and excitoxicity are fundamentally

inter-related. The three conditions are both cause and effect one

another. This concept helps us understand the possible relationship of

Mauve and oxidative stress, and specifically, a proposed mediating

role of low heme.

 

Regulatory and erythroid heme appear to exist in separate functional

pools. The former is a constituent or co-factor for many enzymes

serving the anti-oxidant defense, prevention of excitotoxicity, or

energy production. These heme-requiring enzymes include: cystanthione

synthase, catalase, heme-hemopexin (translation of metallothionein),

pyrrolase, guanylate cyclase, the cytochromes, and sulfite reductase.

Regulatory heme levels must be sufficient to sustain zinc, vitamin A,

and melatonin levels. Cell differentiation, response to growth factors

and resistance to viral infections depends on sufficient heme.

Cellular heme levels are lowered by toxins such as gasoline, benzene,

arsenic and cadmium.

 

Graham demonstrated in animals that intraperitoneal OHHPL lowers

microsomal heme levels by 42% within 48 hours of administration.

(Cytochrome p450, which contains heme, was lowered by 50%). If

operative in humans at relevant concentrations, heme depression may be

a major toxic mechanism for Mauve, with important implications about

zinc and oxidative stress. Ames demonstrated that equivalent

experimental heme suppression in cultured brain cells decreased

intracellular zinc by 50%. Ames further found increases in pro-oxidant

iron, decreased mitochondrial Complex IV (which requires heme), and

significantly increased nitric oxide production after experimental

heme suppression of similar magnitude.

 

It is noted that heme synthesis depends on sufficient vitamin B6 and

zinc. In addition, Durko demonstrated in 1970 that oxidized

kryptopyrrole, very similar to OHHPL, binds heme in vitro.

 

On the preceding bases, a first hypothesis: Mauve may be a significant

contributer to oxidative stress, so may be a good biomarker for

oxidative stress.

 

Preliminary data from Austria (Lauda) demonstrate a modest negative

correlation between red cell glutathione and urinary Mauve by

colorimetric assay. A significant inverse correlation exists between

GST and urinary Mauve by colorimetric assay, and pends publication

(correlation coefficient -0.65087, p<0.02). Audhya found very strong

inverse correlation (coefficient -0.973) between OHHPL by HPLC/MS and

biotin concentration, also pending publication. It is observed that

biotinidase, which maintains biotin levels, is very sensitive to

oxidative stress.

 

A second hypothesis: Mauve may be a product of oxidation tissue

injury. In the case of high-Mauve schizophrenics, Bibus demonstrated

significant depletion of red-cell membrane arachidonic acid. It is

well-established that oxidative attack on arachidonic acid forms

isolevuglandins, which attack protein lysinyl groups to form pyrrolic

tissue adducts. These pyrrolic adducts consistently autoxidize to take

the hydroxylactam configuration as in Mauve. Generation of OHHPL from

the pyrrolic adduct would require oxidative scission and

decarboxylation of the pyrrolic side-chains. The latter steps are not

without known biochemical parallel, nor is disassociation and urinary

excretion off the monopyrrole, as in hexane poisoing.

 

The Mauve Factor warrants greater usage by clinicians and more

research. There is a need for controlled therapeutic trials of

existing treatments and potential new interventions, particularly

anti-oxidants. Suspected pro-oxidant and excitotoxic properties of

OHHPL should be elucidated in the laboratory. The origin and genetics

of Mauve are considered important areas of inquiry.

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