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Urinary pyrrole (Mauve Factor): marker for oxidative stress in behavioral disorders

Urinary pyrrole (Mauve Factor): marker for oxidative stress in behavioral disorders. Woody McGinnis MD mcginnis@mind.net Seattle, 6 November 2004. The Mauve Factor. CH 3. C 2 H 5. OHHPL (hydroxyhemopyrrolin-2-one). OHHPL (Mauve Factor). In human urine, blood and CSF

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Urinary pyrrole (Mauve Factor): marker for oxidative stress in behavioral disorders

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  1. Urinary pyrrole (Mauve Factor): marker for oxidative stress in behavioral disorders Woody McGinnis MD mcginnis@mind.net Seattle, 6 November 2004

  2. The Mauve Factor CH3 C2H5 OHHPL (hydroxyhemopyrrolin-2-one)

  3. OHHPL (Mauve Factor) • In human urine, blood and CSF • Mistakenly identified as kryptopyrrole, a persistent erroneous term • Chemically similar to kryptopyrrole, which can be used for OHHPL assay

  4. HP KP CH3 C2H5 C2H5 CH3 OHHPL OHKPL CH3 C2H5 C2H5 CH3

  5. Mauve history • Discovered in urine in 1957 • Named for lilac-colored appearance on paper chromatograms developed with Erhlich's reagent • Labile and elusive • Abram Hoffer is the father of Mauve

  6. Hoffer Irvine Osmond Pfeiffer Sohler Cutler O'Reilly Graham Riordan Jackson Walsh Audhya Europe Mauve Hall of Fame

  7. Hoffer J Neuropscyh 1961 • Qualitative Mauve assay • All normals mauve-negative • 27/39 early schizophrenics positive • All 7 who recovered on niacinamide converted to negative

  8. Hoffer 1961 • Relapses associated with reappearance of Mauve • Apparent role in other behaviors: ETOH, depression. • A "mentally retarded" mauve-positive child responded dramatically to niacinamide

  9. Hoffer and Mauve • Heat and light sensitive • Relatives should be tested • Preventive potential • 10/14 criminal / deviant positives • Report on 740 patients in 1966 • All recovered schizophrenics negative, unrecovered 50% positive

  10. O'Reilly 1965 • Report on 850 behavioral patients • 25% of "disturbed children" mauve-positive, vs 12% of well children • First documented observation of Mauve association with stress

  11. Mauve in schizophrenia • Hoffer 1961, 1963, 1966 • Yutwiller 1962 • O'Reilly 1965 • Sohler 1967 x 2

  12. High-Mauve and behavior • Down syndrome 70% • Schizophrenia 40-70% • Autism 50% • ADHD 30% • ETOH 20-80%

  13. Carl Pfeiffer 1972 • "Sara" 15 y.o. with four years of unreality spells, insomnia, seizures, attempted suicides, knee problems; quite well on B6 1000 mg, Zn 160 mg, Mn 8 mg. • Signs, symptoms, and clinical response imply high B6 / zinc need in high-Mauves. • B6 and zinc quickly recognized by clinicians as main-stay treatment.

  14. Mauve levels • Clinicians: behavioral symptoms in individuals correlate with level • Irvine 1972: likelihood of depressive reactions correlate with level • Cutler 1974: B6 dose needed to normalize Mauve proportional to level • McCabe 1983: Mauve can be normalized with high-dose B6 only

  15. Pfeiffer 1983 • Symptoms may improve in 24 hours, usually within 1 week • May need months for full recovery • Relapse within days or weeks if no nutrients • Changing needs

  16. OHHPL Levels and B6 (10mg/kg/day) + Zn (25mg) + Mg (400mg) in Autism

  17. Nail spots Stretch marks Pale skin Poor tanning Knees and joints Constipation Dream recall Morning nausea Light and sound Odor intolerance Migraines Stitch-in-side Pfeiffer correlates

  18. Walsh Low stress tolerance Anxious, overly pessimistic Explosive anger Hyperactivity Kruesi Social withdrawal Emotionally labile Loss of appetite Fatiguability

  19. Mauve and stress • Mauve is associated with stress, including, emotional stress. Audhya 1992. Cold-immersion increased Mauve <1 hour • The correlation is well-documented over decades

  20. Mauve and stress O'Reilly 1965 Sohler 1971 Pfeiffer "stress-dosing" 1973 Ward says across all diagnoses 1975 Hippchem 1978 McCabe 1983 Jaffe and Kruesi 1992

  21. Non-behavioral Mauve • Acute Intermittent Porphyria • Cutler 1974: High-mauve obesity and abnormal glucose tolerance • Hoffer 1966: 33/99 Cancer patients, 7/8 lung cancer patients • Riordan and Jackson: 43% of general medical patients: arthritis, chronic fatigue, heart disease, hypertension, irritable bowel, migraine. Range 20-40 mcg%.

  22. Mauve bumps in the road • U Michigan 1962: no pathological importance in schizophrenia because found 34% Mauve-negative. • U Cal 1969: their "simplified" assay produced phenothiazine false-positive • India 1971: No Mauve in 120 psych patients--used HCl, 24° collection.

  23. More bumps in the road.. • Am J Psychiatr 1978: "Pyroluria a poor marker in chronic schizophrenia" (based on 2/9 Mauve-positives) • J Nutr 1979: "..urinary kryptopyrrole..proved invalid as screening test for vitamin dependent disorders.." (based on 6/20 Mauve-positives, all borderline. And no zinc.)

  24. Bumps • U Cal 1975: "Non-occurrence of kryptopyrrole and hemopyrrole in urine of schizophrenics by GC-MS" • UC Berkeley 1978: GC/MS shows no kryptopyrrole or hemopyrrole in schizophrenics or controls • Irvine 1977-78 confirms Mauve is OHHPL by synthesis.

  25. Bumps.. • Irvine, Nature 1969: Mauve identified unequivocally as kryptopyrrole • Irvine, in landmark OrthomolecularPsychiatry, "Mauve is kryptopyrrole" • Irvine 1974: lactam of kryptopyrrole is the "identity of the natural kryptopyrrole"

  26. Was Pfeiffer right about Mauve and low zinc? Walsh. 1148 ADHD patients: Plasma Zn vs colorimetric Mauve Strong negative correlation 0.974 significance (F test)

  27. OHHPL vs. RBC Zinc Correlation Coefficient -.985

  28. Mauve vs WBC Zinc Correlation Coefficient -.743

  29. Mauve as clinical tool • Careful specimen collection • Mild 20-30, moderate 30-40, severe over 40 mcg% • Elevations imply zinc and B6 need • Titrate nutrients to suppress Mauve • Individualize adjunctive nutrients

  30. Mauve is OHHPL • Graham, Univ Glasgow 1978 quantified normal range by GLC • Audhya 1994-present: commercial OHHPL by HPLC/MS and synthetic standard. • Strong logical imperative to cease "kryptopyrrole" terminology

  31. OHHPL facts • Irvine 1977: levels correlate with emotional withdrawal, motor retardation, blocked affect and severe depression; IP to rats: ptosis, locomotor aberration, hypothermia • Cutler 1990: IP to mice increased backward locomotion and head-twitching (as with psychotomimetics)

  32. OHHPL facts • Photo, heat, and acid-labile • Urinary half-life 10-12 hours • Nearly 100% urinary clearance intact after IP administration • Daily excretion up to 1 mg • Urine, Blood, CSF; animal brain • Graham: similarity to kainic acid and pyroglutamate suggests excitoxicity

  33. Why do they both work? Niacinamide (B3) OR Vitamin B6 (P5P) and Zinc

  34. Thinking points • B3, Zn and B6 are anti-oxidant • Strong stress / Mauve association • Emotional stress clearly causes oxidative stress • The behavioral and somatic high-Mauve disorders feature high oxidative stress

  35. High Oxidative Biomarkers • Down Syndrome • Schizophrenia • Autism • ADHD • Emotional Stress • Cancer and Inflammatory Disease • Hyperglycemia

  36. Zinc is anti-oxidant • Shields -SH groups • Blocks lipid peroxidation and PLA2 • Induces metallothionein • Constituent of SOD • Maintains vitamin A • Deficiency increases intestinal NO˙

  37. Zinc deficiency increases oxidative stress • Lower glutathione, vitamin E, GST, GSHPx and SOD • Increased reactive species and lipid peroxides in tissue, membranes and mitochondria

  38. Oxidants mobilize zinc • Oxidants release complexed zinc from zinc-binding proteins, including metallothionein and albumin • It is likely--but unproven--that zinc retention is reduced in direct relationship to oxidative stress

  39. Oxidative stress Low zinc

  40. B6 is anti-oxidant • P5P for Glutathione, Metallothionein, CoQ10 and Heme synthesis • With Zn, cofactor for GAD • P5P protects vulnerable lysinyl groups, as in GSHPx

  41. Marginal B6 deficiency: Lowers GSHPx Lowers glutathione reductase Promotes mitochondrial decay Raises lipid peroxide levels

  42. B6 and oxidative stress • Binding of P5P-dependent enzymes is subject to carbonyl inhibition • Binding of key P5P-dependent enzymes such as GAD impaired by oxidants generally • OH˙ and 1O2 attack B6 vitamers

  43. B6 and Mauve • B6 levels are normal • Pfeiffer alluded to lower P5P and EGOT activity in high-Mauves • Lower zinc may impair B6 activation • Oxidative stress affects activation of B6 and binding of B6-dependent enzymes

  44. B3 is anti-oxidant • NADPH for reduction of glutathione • Potent free-radical quencher: protects both lipids and proteins from oxidation • Blocks NO˙ neurotoxicity • High tissue levels: better lipoxidation prevention than ascorbate

  45. B3 is anti-oxidant • Niacin antagonists increase lipoxidation • Low B3 decreases MT and increases apoptosis in brain cells • Neuroprotective in experimental mitochondrial toxicity

  46. Reciprocal relationships Oxidative stress Poor energeticsExcitotoxicty

  47. Cystathionine synthase Catalase Heme-hemopexin for MT translation Pyrrolase Guanylate cyclase Cytochromes Sulfite reductase NOS Require heme

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