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Pyroluria: Hidden Cause of Schizophrenia, Bipolar, Depression,
and Anxiety Symptoms
by Woody McGinnis, M.D.
Orlando 21 May 2004
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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
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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