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Oxidative stress in_behavioral_dsiorders

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  • 1. Urinary Pyrrole (Mauve Factor): Metric for Oxidative Stress in Behavioral Disorders Woody R. McGinnis M.D. Urinary pyrrole, “Mauve Factor” for its chromatographic appearance, was found elevated in 60% of schizophrenics four decades ago by Hoffer, who reported that high doses of niacinamide lowered pyrrole levels, and that symptoms improved accordingly. Pfeiffer introduced successful treatment with zinc, vitamin B6 and generous anti-oxidants. Many thousands of patients have responded to these approaches, often dramatically. The frequency of elevated pyrrole is 70% in Down syndrome O OH (Jackson, Riordan), 50% in autism (Audhya), 40% in alcoholism COOH (Mathews-Larson), and 30% in ADHD (Walsh). Irrespective of l behavioral diagnosis, elevation is associated with poor tolerance of physical and emotional stress, which increases urinary levels O IsoLevuglandin E2 and necessitates dosing adjustments. Low red cell (Audhya) and white cell (McLaren-Howard) zinc levels correlate with pyrrole protein-NH levels, as do zinc (and B6) requirements, which may be great. Mauve Factor is unstable in presence of light, and was mis- O OH identified as kryptopyrrole (KP) until improved technology in 1976 COOH established that hydroxyhemopyrrolin-2-one (HPL), a hydroxy- protein-- N lactam of hemopyrrole, is Mauve Factor, or at least its key moiety. Laboratories use KP or HPL as standard for this economical test. Schiff base HPL inhibits heme synthesis (Graham). Experimentally, heme inhibition results in lower cellular zinc, and higher iron and oxidative- stress levels (Ames). Heme-dependent enzymes, which play OH key roles in anti-oxidant defense, include catalase, peroxidase, COOH protein-- N NO-synthase, cystathionine synthase, heme-hemopexin (synthesis of metallothionein), p450, and cytochromes for energy production. Pyrrole Mauve Factor is strongly associated with depletion of arachidonic acid (Bibus), which is attacked by free radicals to form levuglandins and isolevuglandins, which in turn produce pyrrolic tissue adducts. These pyrrolic adducts consistently auto-oxidize to form a hydroxy- OH HO lactam (Salomon), and the pyrrolic moiety of these adducts corres- COOH ponds precisely to the structure of HPL. Urinary pyrroles are known protein-- N to result from the formation of pyrrolic tissue adducts (Batoreu). O Hydroxylactam Thus, Mauve Factor appears to derive from oxidative injury to Boxed-area is HPL (Hydroxyhemopyrrolin-2-one), putative Mauve Factor lipid and protein. Current research seeks to correlate Mauve Factor with glutathione, GSH-peroxidase, lipoperoxide, isoprostane, and apoptosis levels. The clinical experience with Mauve Factor in the abnormal behaviors should heighten interest in the causal role of oxidative stress and advance treatment for these disorders.

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