Back to 1997 4th Quarter Table of Contents


The Journal of Orthomolecular Medicine Vol. 12, 4th Quarter 1997

Peroxisomal Disturbances in Autistic Spectrum Disorder

Patricia C. Kane, Ph.D.; Edward Kane

Download The Full Text Article in (PDF)

Back to 1997 archives

Back To Archive Home Page

Subscribe to the JOM


Abstract

Children presenting with Autistic Spectrum Disorder have challenged medical science, yet prolific research has not answered the cause, appropriate testing or treatment of these patients. To determine the etiology of children with autistic features we investigated metabolic aberrations through profiling blood chemistry, organic and amino acids, and red cell membrane fatty acids. Our findings of the red cell membrane analysis of 50 subjects reveal characteristic elevation of the very long chain fatty acids (VLCFAs) above C22 as Nervonic (C24:1w9), Lignoceric (C24:0), Docosapentaenoic (C22:5w3) and Docosahexaenoic (C22:6w3) indicating peroxisomal involvement. Peroxisomal disorders are characterized by an accumulation in tissue and body fluids of metabolites that normally are degraded in the peroxisome including saturated and unsaturated VLCFAs and the branched chain fatty acids, pristanic and phytanic. Peroxisomes are pivotal in the biotransformation of endogenous compounds in lipid metabolism as fatty acids, steroids, prostaglandins, the formation of myelin impacting the immune, endocrine and central nervous systems in addition to the detoxification of exogenous compounds and xenobiotics. The accumulation of VLCFAs are indicative of defects in peroxisomal ßoxidation which may explain the deleterious effects to the brain, endocrine and immune systems and hepatic cytochrome P450 derangement characteristic in autistic spectrum disorder.

Introduction

Profound neurodegenerative conditions observed in autistic spectrum disorder (ASD) with or without seizures in

  1. Bio Body Centre, Five Osprey Dr., Millville, NJ 08332

  2. Carbon Based, P.O Box 809, Millville, NJ 08332

pediatric patients can be attenuated with metabolic intervention if unique aberrations in red cell fatty acid analysis are carefully profiled through a medical data management system and attenuated specific to unique fatty acid disturbance. Our theoretical model suggests that because children with ASD present with a wide variation of soft signs of metabolic derangement, many aspects of an individual’s biochemistry must be evaluated and metabolically modeled. Our interpretation of findings are based on this metabolic model with the evaluation of energy generation and transfer in the forefront due to the aberrant findings in our study participants which can be traced to a secondary method of energy generation riveted within altered fatty acid metabolism ultimately impacting the peroxisomal organelles.

A new frontier in medicine has awakened in the exploration of three dimensional metabolics through red cell fatty acid analysis opening a therapeutic window in time—a two month view—into cell membrane dynamics. The bilipid layer surrounding every cell and organelle is far more than a protective shield; it is the very essence of life, with vibrant electrical activity providing gates in and out–a bewildering array of receptors for opening and closing the bilipid layer for ingress and egress–a dazzling assembly of signaling devices that literally control and signal all activities of membrane traffic inside and out. Red cell fatty analysis leads the clinician into a wide realm of metabolic strategies to influence the health of the patient. Lipids evolve into hormones, immune components, leukotrienes, prostaglandins, cytokines, and myelin–there is virtually no system of the body that does not require attenuation of specific fatty acid substrates and coenzymes to maintain health and repair of body tissues. The turmoil over which specific lipid substrates to administer for therapeutic application to fulfill individual need has always been a loaded question that has led physicians to an awkward gunshot approach (just add flax oil to the diet) that has often failed us therapeutically. It is prudent that the specific essential fatty acid needs of patients be addressed in a scientific manner so that favorable clinical outcomes might be reached.

Clinical application of research data often has left physicians frustrated on timely introduction of new testing methods and metabolic support directly to patients. Children with ASD present an even greater frustration due to the complexity of their illness. Clinical lab results are redefined through Carbon Based computation of raw data offering the physician metabolic strategies that may be applied immediately. In the case of two year old Alex, his parents were gravely concerned over their child’s diagnosis of autism. His parents and doctor were interested in biochemical intervention, but were unsure how to assess the disturbed metabolism and immune insufficiency. We suggested initial labs of a Chemistry Panel-28 including a CO2, Complete Blood Count with differential, and a Red Cell Membrane Fatty Acid Analysis from Kennedy Krieger Institute Peroxisomal Diseases Lab. Alex’s red cell membrane fatty acid test results revealed strident elevation of Docosapentaenoic w3, Docosahexaenoic, Lignoceric, Arachidonic and Nervonic acids (Table 1, p. 209). Alex’s blood chemistry was also sharply altered (view Alex’s complete blood chemistry before and after nutrient therapy Table 2, p. 210, Table 3, p. 211) with derangement in his hematology, mineral balance, nitrogen retention, electrolyte and immune parameters. Alex’s parents and doctor were able to begin immediate administration of appropriate nutrient therapy and directed nutriture with receipt of Alex’s lab results run through the Carbon Based system. The child required substantial digestive support, mineral repletion, oral electrolytes, cofactors, and targeted lipids. Within three months of metabolic intervention Alex had made remarkable strides in speech (absence of speech to 48 words), eye contact, appropriate play, social interaction and gross motor skills. Eight months of targeted nutrient support through blood chemistry and lipid evaluation yielded complete cessation of autistic features (see comparison report Table 4, p. 212).

Methods

Collection of data involved the aquisition of pertinent blood and urine specimens for analysis of blood chemistry, hematology, organic acids, amino acids and red cell membrane fatty acids along with complete medical records and an extensive 35 page questionnaire of the child’s history including pictures and video footage of child’s developmental delay and medical condition. Blood chemistry and hematology specimens were sent to LabCorp in Reno, Nevada, Urine and plasma organic acids and amino acids (mass spectrometry) to Saint Louis University Metabolic Screening Lab, and RBC fatty acid analysis (gas chromatography) to Kennedy Krieger Institute Peroxisomal Diseases Laboratory in Baltimore, Maryland. In depth computational data analysis and graphical representation from Carbon Based Corporation in Incline Village, Nevada was utilized to evaluate biochemical laboratory results and metabolic interactions of individual patients, a comparative model of the chemistries, drug interactions, and disease patterns. This nexus of modern computational technique with raw data potentiates an exceptional scientific tool enabling medical data to be more fully utilized.

Results

Elongation of very long chain fatty acids in red blood cells as Nervonic (C24:1 w9) and Lignoceric (C24:0) acids indicative of peroxisomal involvement was the most Table 1. Red cell fatty acid membrane analysis of Alex’s blood lipids profile.

Table 2. Alex’s autism. Initial blood chemistry of Alex, age 2, before targeted nutrient therapy.

Table 3. Alex’s autism resolved. Post treatment blood chemistry of Alex, age 3, after targeted nutrient therapy.

Table 4. Comparison report of blood profile of Alex before and after targeted nutrient therapy. The arrow’s length is proportional to change. Left is increased; right is decreased; White is an improvement; black is a decline.

prominent and consistent feature in every subject tested, with 39 out of 50 subjects also exhibiting elevation of Docosapentaenoic (C22:5w3) and Docosahexaenoic (C22:6w3), in 41 of 50 subjects Arachidonic (C20:4w6) and 20 of 50 subjects elevation of Eicosapentaenoic (C20:5w3). Depression of fatty acids in red blood cells included 30 out of 50 subjects (primarily subjects with profound autistic features) with supression of Eicosapentaenoic (C20:5w3) and 50 out of 50 subjects with suppression of Gamma Linolenic (C18:3w6) and Dihomogamma Linolenic (C20:3w6).

Treatment

Subjects with elevation of VLCFAs required detailed manipulation of their individual biochemistry to address fully the buildup of VLCFAs. Children with autistic spectrum disorder were approached initially with stabilization of membrane traffic through examination of their serum electrolytes and subsequent administration of an oral balanced hypertonic electrolyte solution in enteral or oral feeds. Marked disruption in ionic homeostasis pH, anion gap, cellular osmolarity, and the decline of electrolyte gradients across the cell membrane was observed as these patients have grave difficulty balancing the dynamic process of their chemical buffering systems to maintain a constant serum pH. Often there was involvement of all three systems: Carbonic acid-Bicarbonate buffering; Phosphate buffering; and Protein buffering systems. Children with intractable seizure disorders, autistic syndromes and brain injury have improved cognitively when receiving individualized IV electrolyte solutions during hospitalization for illness (as observed by Kane) whereby positive outcomes also were achieved with balanced 9 mEq oral electrolyte solutions. Metabolic intervention also was directed towards lipid manipulation by competitive inhibition,1 inclusion of the lignan sesamin2 and curcumin3 with low CHO diet to suppress insulin4-8 and block delta 5 desaturase synthesis, the administration of coenzymes such as potassium permanganate, riboflavin-5-phosphate,9-10 selenium and hormones11 as dehydroepiandrosterone,12 pregnenolone,13-15 and thyroid16 to stimulate betaoxidation, nutritional adjuncts to stabilize lipids in the cell membrane17-25 such as ginger, oral balanced electrolytes and alteration of the diet to increase nutrient density, avoidance of VLCFAs in food intake, and supplementation of depressed fatty acids26 (determined from red cell testing) such as evening primrose oil27 to address suppression of GLA/DGLA and long chain fatty alcohols to stimulate plasmalogen synthesis.28,29

Conclusions

Derangement of lipid metabolism primarily of peroxisomal ßoxidation was observed in children with seizure disorders,30 autism,30 ASD with enlarged neurons,31 and hypoxic brain damage32 with sharp elevation of VLCFAs with elevation of Lignoceric, Nervonic, Docosahexanoic, and depression of Hexacosanoic. Conversely, boys with X-Linked Adrenoleukodystrophy exhibit elevation of serum and red cell Lignoceric and Hexacosanoic acids33 with depression of Docosahexaenoic34 and Nervonic acids.35 Peroxisomal disorders are characterized by an accumulation in tissue and body fluids of metabolites that normally are degraded in the peroxisome including saturated and unsaturated VLCFA,33, 36-41 branched chain fatty acids, pipecolic, phytanic and pristanic acids, and bile acid intermediates dihydroxy- and trihydroxycoprostanic acid, (DHCA and THCA respectively). Peroxisomal disorders with a clinical onset of four years of age may present as behavioral changes, intellectual deterioration, and visual impairment. Accumulation of VLCFAs42 are associated with a deficiency of the fatty acyl-CoA oxidase (AOX), the enzyme that catalyses the first step in ßoxidation. A prerequisite for ßoxidation is the activation of fatty acids to their Co-A derivatives.43-45 Peroxisomes and mitochondria degrade saturated and unsaturated fatty acids via similar reactions with the same acyl-CoA intermediates formed, but there are distinct differences between the two systems.46-48 Very long chain acyl-CoA synthetase activity is present in the endoplasmic reticulum and proposed to be in the peroxisomes, but not in the mitochondria.49-52 Long chain fatty acids are preferentially oxidized in the mitochondria,53-55 but VLCFAs are oxidized predominantly, if not exclusively in some tissues by peroxisomes.56,57 Compared to long chain fatty acids (in mitochondria), the VLCFAs are only slowly oxidized by isolated peroxisomes. VLCFAs enter the peroxisome58 and are shortened to long chain fatty acids, transferred back to the mitochondria,59 then further oxidized in mitochondria, esterified in the endoplasmic reticulum or perhaps partly in the peroxisome itself. The accumulation of VLCFA may constitute a minor part of overall fatty acids, but peroxisome deficiency disorders are deleterious to the brain and CNS.33,60 Autism and seizure disorders may mimic pseudo-neonatal adreno-leukodys-trophy61,62 as a peroxisomal disorder with enlarged peroxisomes30,31 and a specific deficiency of acyl-CoA oxidase.63,64 Peroxisomes, present in virtually all cells, but most prevalent in the liver and kidney play a critical role of cellular lipid metabolism in the biosynthesis of fatty acids via ßoxidation65-69 involving physiologically important substrates for VLCFA, dicarboxylic fatty acids, prostaglandins, thromboxanes, leukotrienes, pristanic acid, DHCA, THCA, and xenobiotics.70,71 Children with autistic spectrum disorder often present with complex xenobiotics involving disturbances in the cytochrome p450 superfamily which parallels disturbances in peroxisomal function.72-82 The cytochrome p450s are responsible for the biotransformation of endogenous compounds including fatty acids, steroids, prostaglandins, leukotrienes and vitamins as well as the detoxification of exogenous compounds resulting in substantial alterations of p450s as xenobiotics may turn off or greatly reduce the expression of constitutive isoenzymes. The overzealous administration of tocopherols may actually worsen the condition of autism as vitamin E is a potent antioxidant that supresses beta-oxidation of the very long chain fatty acids.

Elevation of Docosahexaenoic acid (DHA)83-85 in red cell fatty acid analysis found in many of our subjects with autistic spectrum disorder may involve the cytochrome p450 enzyme Nitric Oxide Synthase (NOS) and Nitric Oxide (NO) formation in that supplementation of DHA augments NO generation.86 Nitric oxide inhibits beta oxidation of lipids and thereby stimulates the buildup of VLCFAs. Nitric oxide is the smallest biologic product of human cells, critically involved in the modulation of cerebral blood flow, blood pressure, electrolytic balance, platelet adhesion, hormonal release, insulin secretion, synaptic plasticity, immunity, neurotransmission, neuromodulation, gastrointestinal and hepatic function.

Cerebral injury or hypoxia mediates an excess of the neurotransmitter glutamate which acts at the NMDA subtype receptor to open Ca2+ channels creating an increase in NO release with inducible NOS activity (there are three isoforms of NOS, inducible NOS is Ca dependent) detected in immune cells within the brain and elevation of cGMP levels.87 The synthesis of NO by neurons has finite regulation and NO’s reactions vary widely with pH. Nitric oxide has a high affinity for hemoglobin and NO is rapidly inactivated by binding to hemoglobin in that its physiological actions remain localized to the site of its generation and its actions are in general rapidly terminated. This phenomenon may explain why many subjects in our study exhibited sharp elevation of hemoglobin, iron and RBCs yet presented with a “china doll complexion” (aptly described by Carl Pfeiffer). Nitric oxide activity can be prolonged by forming nitrothiols with serum albumin88 acting as an NO carrier. Thus the consistent sharp elevation of albumin in our subjects may be understood in that nitrothiols may act as a store, prolonging the actions of released NO or as an additional “biological sink” for NO which regulates the concentration of free NO. While Arachidonic acid induces cyclooxygenase (COX) activity, nitric oxide specifically inhibits COX-2. As nitric oxide binds to heme, therapeutic modalities may be applied to reach COX-2 expression whereby expression of COX-2 may dictate the balance between TH1 and and TH2 cells presently being investigated in ASD.

Eicosapentaenoic acid (EPA) down-regulates tumor necrosis factor having profound immunomodulatory properties. Perhaps the pivotal issue as to why children with pervasive developmental delay and autism do not respond appropriately to administration of marine oils is that they are unable to beta oxidize DHA into EPA or convert EPA into series three prostaglandins.

Our findings indicate that the electrolyte disturbances (primarily involving elevation of calcium with depression of carbon dioxide, elevation or suppression of sodium and potassium), altered hematology, compromised nitrogen status (low creatinine, elevated albumin) and elevation of red cell fatty acids Docosahexaenoic, Docosapentaenoic w3, Arachidonic, Nervonic and Lignoceric may serve as crucial markers in neurodegenerative conditions leading to clarification of the etiology of autistic syndromes and complex seizure disorders by approaching metabolic derangement through targeted lipids, long chain fatty alcohols, pregnenolone (only after appropriate lipid therapies have been administered), oral electrolytes, coenzymes (vitamins and minerals as cofactors), and dietary manipulation (elemental dietary measures). Autism is a systemic disorder that has plagued yet intrigued us for decades. To unravel autism inspires us to view medical disorders and disease from both a microcosmic and macrocosmic biochemical perspective. By capturing cell membrane dynamics we now have an individualized, targeted therapeutic approach to ease the entropy of disturbed metabolism.

References

  1. Rubin D, Laposata M: Cellular interactions between n-6 and n-3 fatty acids: a mass analysis of fatty acid elongation/desaturation, distribution among complex lipids, and conversion to eicosanoids. J Lipid Research ,1992: 33; 1431-14

  2. Umeda-Sawada R, Takahashi N, Igarashi O: Interaction of sesamin and eicosapentaenoic acid against delta 5 desaturation and n-6/n-3 ratio of essential fatty acids in rat hepatocytes. Biosci Biotechnol Biochem (JAPAN) Dec 1995: 59: 12: 2268-73.

  3. Fujiyama-Fujiwar Y, Umeda R, Igarashi O: Effects of sesamin and curcumin on delta 5-desaturation and chain elongation of polyunsaturated fatty acid metabolism in primary cultured rat hepatocytes. J Nutr Sci Vitaminol (Tokyo) (JAPAN) 1992: 38/4; 353-63.

  4. Xu L, Ash M, Abdel-Aleem S, Lowe JE, Badr M: Hyperinsulinemia inhibits hepatic peroxisomal ßoxidation in rats. Hormone Metabolism Research. 1995: 27; 76-78.

  5. Yavin E, Kunievsky B, Bazan NG, Harel S: Regulation of arachidonic acid metabolism in the perinatal brain during development and under ischemic stress. In eds. Bazan NG et al. Neurobiology of Essential Fatty Acids. New York: Plenum Press, 1992.

  6. Schepers L, Casteels M, Vamecq J, Parmentier G, Van Veldhoven PP, Mannaerts GP: ßoxidation of the carboxyl side-chain of prostaglandin E2 in rat liver peroxisomes and mitochondria. J Biol Chem. 1988: 2724-2731.

  7. Gordon JA, Heller SK, Rhead WJ, Watkins PA, Spector AA: Formation of a novel arachidonic acid metabolite in peroxisomes prostaglandins leukotrienes and essential fatty acids. 1995: 52; 77-81.

  8. Bazan NG, Murphy MG, Toffano G: Neurobiology of Essential Fatty Acids. Advances in Experimental Medicine and Biology. 1991: vol 318. Plenum Publishing, New York, 1992.

  9. Amtozzo C, Garavaglia B, Mora M, Rimoldi M, Morandi L, Ursino E, DiDonato S: Late-onset

riboflavin-responsive myopathy with combined multiple acylcoenzyme a dehydrogenase and respiratory chain deficiency. Neurology, 1994: 44; 2153-2158.

  1. Rhead W, Roettger, Marshall T, Amendt B: Multiple acylcoenzyme a dehydrogenation disorder responsive to riboflavin: substrate oxidation, flavin meabolism, flavoenzyme activities in fibroblasts. Pediatric Research. 1993: 33; 2.

  2. Issemann I, Green S Activation of a Member of the Steroid Hormone Receptor Superfamily by Peroxisome Proliferators. Nature 1990: 347; 645-650.

  3. Wu HQ, Masset-Brown J, Tweedie DJ, Milewich L, Frenkel RA, Martin-Wixtrom C, Estabrook RW, Prough RA: Induction of microsomal NADPH-cytochrome P450 IVAI by dehydroepiandrosterone in rats: A possible peroxisomal proliferator. Cancer Research. 1991: 49; 233-243.

  4. Flood JF, Morley JE, Roberts E: Memory enhancing effects in male mice of pregnenolone and steroids metabolically derived from it. Proc Natl Acad Sci USA 1992: 89: 1567-1571.

  5. George MS, Guidotti, Rubinow D, Pan B, Mikalauskas K, Post RM: CSF neuroactive steroids in affective disorders: pregnenolone, progesterone, and DBI Biol Psychiatry 1994: 35: 775-780.

  6. Wu FS, Gibbs TT, Farb DH: Pregnenolone sulfate: a positive neuromodulator at the NMDA receptor. Molec Pharmacol. 1991: 40: 333-336.

    1. Kerckaert I, Claeys A, Just W, Cornelis A, Roels

    2. F: Automated image analysis of rat liver peroxisomes after treatment with thyroid hormones: changes in number, size and catalase reaction. Micron Microsc Acta 1989: 20; 9-18.
  7. Wiseman H: Dietary Influences on Membrane Function. J Nutr Biochem. 1995: 7: 2-15.

  8. Clandinin MT, Jumpsen J, Suh M: Relationship between fatty acid accretion, membrane composition and biological functions. J Pediat. 1994: 125: 5-S25-S32

  9. Kamp F, Zakin D, Zhang F,Noy N, Hamilton JA: Fatty acid flip-flop in phospholipid bilayers is extremely fast. Biochemistry, 1995: 34; 11928-11937.

  10. Kamp F, Hamilton JA: pH gradients across phospholipid membranes caused by fast flip-flop of unionized fatty acids. Proc Natl Acad Sci, 1992: 89; 11367-11370.

  11. Thompson GA: The Regulation of Membrane Lipid Metabolism. Boca Raton, FL, CRC Press: 1992

  12. Slabas AR, Brown A, Sinden BS, Swinhoe R, Simon JW, Ashton AR, Whitfeld PR, Elborough KM: Pivotal Reactions in Fatty Acid Synthesis Prog Lipid Research, 1994: 33:1/2:39-46.

  13. Horrobin DF: DNA-protein and membranelipid: competing paradigms in biomedical research. Med Hypotheses. 1995: 44/4; 229-232.

    1. Trigatti BL, Gerber GE: The effect of intracellular ph on long-chain fatty acid uptake in 3t3-L1 adipocytes: evidence that uptake involves the passive diffusion of protonated long-chain fatty acids across the plasma membrane. Biochem J 1996: 313; 487-494.

    2. McNew JA, Goodman JM: The targeting and assembly of peroxisomal proteins: some old rules do not apply. TIBS, 1996: 21; 54-58.

    26.Collier GR, Sinclair AJ:Role of n-6 and n-3 fatty acids in the dietary treatment of metabolic disorders. Annals NY Acad Sci, 1993: 322-329.

    1. Horrobin DF: Nutritional and medical importance of gammalinolenic acid. Prog Lipid Res 1992: 31/2; 163-194.

    2. Lazarow PB: Peroxisome structure, function and biogenesis-human patients and yeast mutants show stikingly similar defects in peroxisome biosynthesis. J Neuropathol Exper Neurol, 1995: 54/ 5; 720-725.

    3. Damge C et al: Effect of n-hexacosanol on insulin secretion in the rat. Euro J Pharm, 1995: 274; 133-139.

    4. Kane PC, Schauss MA: The Neurochemistry and Neurophysics of Autistic Spectrum Disorder Body Bio Centre: Millville, NJ, 1996

    5. Bauman ML, Kemper TL: The Neurobiology of Autism. Baltimore. Johns Hopkins Univ Press: 1994.

    32. Siesjo BK., Katsura K: In eds. Bazan NG et al Ischemic Brain Damage: Focus on Lipids and Lipid Mediators Neurobiology of Essential Fatty Acids. New York. Plenum Press, 1992.

    1. Moser HW, Moser AB: Very long-chain fatty acids in diagnosis, pathogenesis, and therapy of peroxisomal disorders. Lipids 31: S141-145, 1996.

    2. Martinez M Docosahexanenoic Acid Therapy in Docosahexaenoic Acid-Deficient Patients with Disorders of Peroxisomal Biogenesis Lipids 31:S145-S152,1996

    3. Sargent R, Coupland K, Wilson R: Nervonic Acid and Demyelinating Disease. Medical Hypotheses. 1994: 42; 237-242.

    4. Brown FR, Voight R, Singh AK, Singh I: Peroxisomal disorders. AJDC 147, June 1993.

    5. Singh I, Moser AE, Goldfischer S, Moser HW Lignoceric acid is oxidized in the peroxisome: implications for the zellweger cerebro-hepatorenal syndrome and ALD. Proc Nat Acad Sci 1984: 81; 4203-4207.

    6. Moser AB et al: Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups J Pediat, 1995: 127/1; 13-22.

  1. McGuinness MC, Moser AB, Poll-The BT, Watkins PPA: Complementation analysis of patients with intact peroxisomes and impaired peroxisomal ßoxidation. Biochem Med Metabol Biol, 1993: 49: 228-242.

  2. Nilsson A, Thomassen MS, Christiansen EN: Long chain acylcoa levels in liver from rats fed high-fat diets: is it of significance for an increased peroxisomal ßoxidation? Lipids, 1984: 19; 187-194.

  3. Poggi-Travert F, Fournier B, Poll-The BT, Saudubray JM: Clinical approach to inherited peroxisomal disorders. J Inher Metab Dis Suppl 1995: 18; 1-18.

  4. Wanders RJA, van Roermund CWT, van Wijland MJA et al: Direct demonstration that the deficient oxidation of vlcfa in x-linked ald due to an impaired ability to activate VLCFA. Biochem Biophys Res Commun 1988: 153; 618-624.

  5. Hayashi H, Takahata S: Role of peroxisomal fatty acyl-CoA beta-oxidation in phospholipid biosynthesis. Arch Biochem Biophys, 1991: 284; 326-331.

  6. Aoyama T, Souri M, Kamijo T, Ushikubo S, Hashimoto T: Peroxisomal acylcoenzyme a oxidase is a rate-limiting enzyme in a very-long-chain fatty acid ßoxidation system. Biochem Biophys Res Com, 1994: 201/3; 1541-1547.

  7. Shrago E, Woldegiorgis G, Ruoho AE, DiRusso: Fatty acyl coA esters as regulators of cell metabolism. Prost Leukotr Essent Fatty Acids, 1995: 52; 163-166.

  8. Heuvel JPV, Sterchele PF, Nesbit DJ, Peterson RE: Coordinate induction of acyl-coA binding protein, fatty acid binding protein and peroxisomal ßoxidation by peroxisomal proliferators. Biochemica et Biophysica Acta 1993: 1177; 183-190.

  9. Walton PA, Hill PE, Subramani S: Import of stably folded proteins into peroxisomes Molecular Biology of the Cell, 1995: 6; 675-683.

  10. Van Velhoven PP, Vanhove G, Asselberghs S, Eyssen HJ, Mannaerts GP: Substrate specificities of rat liver peroxisomal acyl-CoA oxidases: palmitoyl-CoA oxidase (inducible acyl-co oxidase), pristanoyl-CoA oxidase (non-inducible acyl-CoA oxidase) and trihydroxy-coprotanoyl-CoA oxidase. J Biol Chem 1992: 267; 20065-20074.

49.Rapoport SI: In vivo labeling of brain phospholipids by long-chain fatty acids: relation to turnover and function. Lipids 1996: 31; S97-S101.

50.Watkins PA, McGuinness MC, Raymond GV, Hicks BA, Sisk JM, Moser AB, Moser HW: Distinction between peroxisomal bifunctional enzyme acyl-CoA oxidase deficiencies. Annals of

Neurology 1995: 38/3; 473-477.

51.Tserng KY, Chen LS, Jin SJ: Comparison of metabolic fluxes of cis-5-enoyl-CoA and saturated Acyl-CoA through the ßoxidation pathway. Biochem J, 1995: 307: 23-28.

  1. Kunau WH, Dommes V, Schulz H: ßoxidation of fatty acids in mitochondria, peroxisomes and bacteria: a century of continued progress. Prog Lipid Res, 1995; 34/4; 267-342.

  2. Singh H, Poulos A: Distinct long chain and very long chain fatty acyl-CoA synthetases in rat liver peroxisomes and microsomes. Arch Biochem Biophys, 1988: 266; 486-495.

54.Lazo O, Contreras M, Singh I: Topographical localization of peroxisomal Acyl-CoA ligases: differential localization of palmitoyl-CoA and lignoceroyl-CoA ligases. Biochemistry, 1990: 29: 3981-3986.

  1. Johnson JK, Kumar NR, Srivastava DK: Molecular basis of the medium-chain fatty acyl-CoA dehydrogenase-catalyzed “oxidase” reaction: pH-dependent distribution of intermediary enzyme species during catalysis. Biochemistry, 1994: 33; 4738-4744.

  2. Jakobs BS, Wanders RJA: Conclusive evidence that VLCFA are oxidized exclusively in peroxisomes in human skin fibroblasts. Biochem Biophys Res Comm, 1991: 178; 842-847.

  3. Lageweg W, Tager JM, Wanders RJA: Topography of VLCFA activating activity in peroxisomes from rat liver. Biochem J, 1991: 276; 53-56.

  4. Rachubinski RA, Subramani S: How proteins penetrate peroxisomes. Cell,1995: 83; 525-528.

  5. Jakobs BS, Wanders RJA: Fatty acid ßoxidation in peroxisomes and mitochondria: the first unequivocal evidence for the involvement of carnitine in shuttling propionyl-coA from peroxisomes to mitochondria. Biochem Biophys Res Com 1995: 213/3; 1035-1041.

  6. Lazo O, Contreras M, Yoshida Y, Singh AK, Stanley W, Weise M, Singh Y: Cellular oxidation of lignoceric acid is regulated by the sub-cellular localization of palmitoyl-CoA and lignoceroyl-CoA ligases. Biochemistry, 1990: 29; 3981-3986.

  7. Poll-The BT, Roels F, Ogier H et al: A new peroxisomal disorder with enlarged peroxisomes and a specific deficiency of acyl-CoA oxidase (pseudo-neonatal adrenoleukodystrophy) Am J Hum Gen 1988: 42; 422-434.

62.Kyllerman M, Blomstrand S, Mansson JE, Conradi NG, Hindmarsh T: Central nervous system malformations and white matter changes in pseudo-neonatal adrenoleukodystrophy. Neuropediatrics, 1990: 21; 199-201.

63.Araki E, Kobayashi T, Kohtake N, Goto I, Hashimoto: A riboflavin-responsive lipid storage myopathy due to multiple acyl CoA dehy-drogenase deficiency: an adult case. J Neurolog Sci, 1994; 126: 202-205.

64.VanHove GF, Van Veldhoven PP, Fransen M, Denis S, Wanders RJA, Mannaerts GP: The CoA-esters of 2-methyl-branched chain fatty acids and of the bile acid intermediates Di- and trihydroxycoprostanoic acids are oxidized by one single Peroxisomal Branched Chain Acyl-CoA oxidase in human liver and kidney. J Biol Chem, 1993: 268; 10335-10344.

  1. Van den Bosch H, Schutgens RBH, Wanders RJA, Tager J: Biochemistry of the peroxisomes Ann Rev Biochem, 1992: 61; 157-197.

  2. Mandel H, Berant M, Aizin A et al: Zellweger-like phenotype in two siblings: A defect in peroxisomal ßoxidation with elevated VLCFA but normal bile acids. J Inher Metab Dis, 1992: 15; 381-384.

  3. Reddy JK: Peroxisomal Lipid Metabolism. Ann Rev Nutr, 1994: 14; 343-70.

  4. Leiper JM, Birdsey GM, Oatey PB: Peroxisomes Proliferate. Trends in Cell Biol, 1995: 5; 435-437.

  5. Diczfalusy U: ßOxidation of Eicosanoids. Prog Lipid Res 1994: 33/4; 403-428.

  6. Mannaerts GP, Van Veldhoven PP: Role of peroxisomes in mammalian metabolism. Cell Biochem Funct. 1992: 10; 141-151.

  7. Van Maldergem L, Espeel M, Wanders RJA et al: Neonatal seizures and severe hypotonia in a male infant suffering from a defect in peroxisomal ßoxidation. NeuroMusc Disord. 1992: 2; 217-224.

  8. Gibson GG, Milton MN, Elcombe CR: Induction of cytochrome p450 via 1-mediated fatty acid hydroxylation: relevance to peroxisome profileration. Biochem Soc Transact, 1990: 18; 97-99.

  9. Gibson GG, Lake B:Peroxisomes: Biology and Importance in Toxicology and Medicine. London. Taylor and Francis, 1993

74.Guengerich FP: Reactions and significance of cytochrome p450 enzymes. J Biol Chem, 1991: 266; 10019-10023.

75.Porter TD, Coon MJ: Cytochrome p450 multiplicity: isoforms, substrates and catalytic and regulatory mechanisms. J Biol Chem, 1991; 266; 13469-13472.

76.Roels F, Espeel M, Poggi F, Mandel H, Van Maldergem L, Saudubray JM: Human liver pathology in peroxisomal diseases: a review including novel data. Biochimie, 1993: 75: 281-292.

77. Sharma R, Lake BG, Foster J, Gibson GG: Microsomal cytochrome p452 induction and peroxisomal proliferation by hypolipidaemic agents in rat liver: a mechanistic inter-relationship. Biochem Pharm, 1988; 37; 1193-1201.

  1. Mandel H et al: A new type of peroxisomal disorder with variable expression in liver and fibroblasts. J Pediat, 1994: 125; 4:549-555.

  2. McGiff JC: Cytochrome p-450 metabolism of arachidonic acid. Annu Rev Pharmacol Toxicol 1991: 31; 339-369.

80.Ram PA, Waxman DJ: DHEA 3 ßsulfate is an endogenous activator of the peroxisome-proliferation pathway: induction of cytochrome p450 4a and acylco oxidase mRNAs in primary rat hepatocyte culture and inhibitory effects of ca++ channel blockers. Biochem J, 1994: 301; 753-758.

81.Luers G, Beier K, Hashimoto T, Fahimi HD, Volki

A: Biogenesis of peroxisomes: sequential bio-synthesis of the membrane and matrix proteins in the course of hepatic regeneration. Euro J Cell Biol, 1990: 52; 175-184.

  1. De Craemer D: Changes in subcellular organelles may influence the peroxisomal shape in human hepatocytes. Biol Cell, 1993: 77: 127.

  2. Marzo I, Alava MA, Pineiro A, Naval J: Biosyn-thesis of docosahexanaenoic acid in human cells: evidence that two different delta 6-desaturase activities may exist. Biochimica et Biophsica Acta, 1996: 1301: 263-272.

  1. Mohan IK, Das UN: Oxidant stress, antioxidants and essential fatty acids in systemic lupus erythematosus. Prostag Leukot Essent Fatty Acids, 1997: 56: 3: 193-196.

  2. Moore SA, Hurt E, Yoder E, Sprecher H, Spector AA: Docosahexaenoic acid synthesis in human skin fibroblasts involves peroxisomal retroconversion of tetracosahexanenoic acid J Lipid Res 1995: 36; 2433-2443.

85.Boulanger C, Schini VB, Hendrickson H, Vanhoutte PM: Chronic exposure of cultured cells to eicosapentaenoic acid potentiates the release of endothelium-derived relaxing factor(s). Brit J Pharmacol, 1990: 99; 176-180.

  1. Lawson DL, Mehta JL, Saldeen K, Mehta P, Saldeen TG: Omega-3 polyunsaturated fatty acids augment endothelium-dependent vaso-relaxation by enhanced release of edrf and vasodilator. Prostaglandins Eicosanoids 1991: 4; 217-223.

  2. Bredt DS, Snyder SH: Nitric oxide mediates glutamate-linked enhancement of CGMP levels in the cerebellum. Proc Natl Acad Sci USA 1989: 86; 9030-9033.

  3. Anggard E: Nitric oxide: mediator, murderer, and medicine, Lancet, 1994: 343; 2299-1206.


[Home] [History] [Library] [Nutrients] [Resources] [Contact] [Contribute]
Back To Molecule

This website is managed by Riordan Clinic
A Non-profit 501(c)(3) Medical, Research and Educational Organization
3100 North Hillside Avenue, Wichita, KS 67219 USA
Phone: 316-682-3100; Fax: 316-682-5054
© (Riordan Clinic) 2004 - 2017

Information on Orthomolecular.org is provided for educational purposes only. It is not intended as medical advice.
Consult your orthomolecular health care professional for individual guidance on specific health problems.