Heme synthesis - note that some reactions occur in the cytoplasm and some in the mitochondrion (yellow)
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Erythropoietic protoporphyria

The porphyrias are inherited or acquired disorders of certain enzymes in the heme biosynthetic pathway (also called porphyrin pathway). They are broadly classified as hepatic porphyrias or erythropoietic porphyrias, based on the site of the overproduction and mainly accumulation of the porphyrins (or their chemical precursors). more...

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Overview

In humans, porphyrins are the main precursors of heme, an essential constituent of hemoglobin, myoglobin, and cytochrome.

Deficiency in the enzymes of the porphyrin pathway leads to insufficient production of heme. This is, however, not the main problem; most enzymes—even when less functional—have enough residual activity to assist in heme biosynthesis. The largest problem in these deficiencies is the accumulation of porphyrins, the heme precursors, which are toxic to tissue in high concentrations. The chemical properties of these intermediates determine in which tissue they accumulate, whether they are photosensitive, and how the compound is excreted (in the urine or feces).

Subtypes

There are eight enzymes in the heme biosynthetic pathway: the first and the last three are in the mitochondria, while the other four are in the cytosol.

  1. δ-aminolevulinate (ALA) synthase
  2. δ-aminolevulinate (ALA) dehydratase
  3. hydroxymethylbilane (HMB) synthase
  4. uroporphyrinogen (URO) synthase
  5. uroporphyrinogen (URO) decarboxylase
  6. coproporphyrinogen (COPRO) oxidase
  7. protoporphyrinogen (PROTO) oxidase
  8. ferrochelastase

Hepatic porphyrias

The hepatic porphyrias include:

  • ALA dehydratase deficiency
  • acute intermittent porphyria (AIP): a deficiency in HMB synthase
  • hereditary coproporphyria (HCP): a deficiency in COPRO oxidase
  • variegate porphyria (VP): a deficiency in PROTO oxidase
  • porphyria cutanea tarda (PCT): a deficiency in URO decarboxylase

Erythropoietic porphyria

The erythropoietic porphyrias include:

  • X-linked sideroblastic anemia (XLSA): a deficiency in ALA synthase
  • congenital erythropoietic porphyria (CEP): a deficiency in URO synthase
  • erythropoietic protoporphyria (EPP): a deficiency in ferrochelatase

Porphyria variegata

Variegate porphyria (also porphyria variegata or mixed porphyria) results from a partial deficiency in PROTO oxidase, manifesting itself with skin lesions similar to those of porphyria cutanea tarda combined with acute neurologic attacks. It may first occur in the second decade of life; there is a cohort of sufferers living in South Africa descended from a single person from the Netherlands, Berrit Janisz, who emigrated in the 17th century.

Signs and symptoms

The hepatic porphyrias primarily affect the nervous system, resulting in abdominal pain, vomiting, acute neuropathy, seizures, and mental disturbances, including hallucinations, depression, anxiety, and paranoia. Cardiac arrhythmias and tachycardia (fast heart rate) may develop as the autonomic nervous system is affected. Pain can be severe and can, in some cases, be both acute and chronic in nature. Constipation is frequently present, as the nervous system of the gut is affected.

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Divergent optimum levels of lycopene, beta-carotene and lutein protecting against UVB irradiation in human fibroblasts
From Photochemistry and Photobiology, 5/1/02 by Eichler, Olaf

Divergent Optimum Levels of Lycopene, beta-Carotene and Lutein Protecting Against UVB Irradiation in Human Fibroblasts(para)

ABSTRACT

Exposure of living organisms to UV light leads to photooxidative reactions. Peroxyl radicals are involved in the propagation of lipid peroxidation. Carotenoids are dietary antioxidants and show photoprotective effects in human skin, efficiently scavenging peroxyl radicals and inhibiting lipid peroxidation. Cultured human skin fibroblasts were used to examine the protective effects of the carotenoids, lycopene, beta-carotene and lutein on UVB-induced lipid peroxidation. The carotenoids were delivered to the cells using liposomes as the vehicle. The cells were exposed to UVB light for 20 min. Lycopene, beta-carotene and lutein were capable of decreasing UV-induced formation of thiobarbituric acid-reactive substances at 1 h to levels 40-50% of controls free of carotenoids. The amounts of carotenoid needed for optimal protection were divergent at 0.05, 0.40 and 0.30 nmol/mg protein for lycopene, beta-carotene and lutein, respectively. Beyond the optimum levels, further increases of carotenoid levels in cells led to prooxidant effects.

Abbreviations: BHT, butylated hydroxytoluene; DMEM, Dulbecco modified Eagle medium; DPPC, 1,2-dipalmitoyl-sn-glycero-phosphatidylcholine; HBSS, Hank's balanced salt solution; HPLC, high performance liquid chromatography; MDA, malondialdehyde; TBARS, thiobarbituric acid-reactive substances.

INTRODUCTION

Acknowledgement-Supported by the Bundesministerium fur Bildung und Forschung, Bonn (Leitprojekt: Verbesserte gesundheitliche Qualitat von Lebensmitteln dutch Carotinoide). O.E. is a stipendiary of the "Graduiertenkolleg Toxikologie and Umwelthygiene" of the Deutsche Forschungsgemeinschaft, Bonn. H.S. is a Fellow of the National Foundation of Cancer Research, Bethesda.

(para)Posted on the web site on 22 February 2002.

*To whom correspondence should be addressed at: Institut fur Physiologische Chemie I, Heinrich-Heine-Universitat DUsseldorf, P.O. Box 101007, D-40001 Dusseldorf, Germany. Fax: 49-211-- 811-3029; e-mail: wilhelm.stahl@uni-duesseldorf.de

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2. Klotz, L. O., N. J. Holbrook and H. Sies (2001) UVA and singlet oxygen as inducers of cutaneous signaling events. Curr. Probl. Dermatol. 29, 95-113.

3. Berneburg, M. and J. Krutmann (2000) Photoimmunology, DNA repair and photocarcinogenesis. J. Photochem. Photobiol. B 54, 87-93.

4. Thiele, J. J., C. Schroeter, S. N. Hsieh, M. Podda and L. Packer (2001) The antioxidant network of the stratum corneum. Curr. Probl. Dermatol. 29, 26-42.

5. Landrum, J. T. and R. A. Bone (2001) Lutein, zeaxanthin, and the macular pigment. Arch. Biochem. Biophys. 385, 28-40.

6. Sies, H. and W. Stahl (1995) Vitamins E and C, 3-carotene, and other carotenoids as antioxidants. Am. J. Clin. Nutr. 62, 1315S1321S.

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8. Mayne, S. T. (1996) Beta-carotene, carotenoids, and disease prevention in humans. FASEB J. 10, 690-701.

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13. Stahl, W., U. Heinrich, S. Wiseman, 0. Eichler, H. Sies and H. Tronnier (2001) Dietary tomato paste protects against UV-induced erythema in humans. J. Nutr. 131, 1449-1451.

14. Mathews-Roth, M. M., M. A. Pathak, T. B. Fitzpatrick, L. C. Harber and E. H. Kass (1970) Beta-carotene as a photoprotective agent in erythropoietic protoporphyria. N. Engl. J. Med. 282, 1231-1234.

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16. Lowe, G. M., L. A. Booth, A. J. Young and R. F. Bilton (1999) Lycopene and beta-carotene protect against oxidative damage in HT29 cells at low concentrations but rapidly lose this capacity at higher doses. Free Radic. Res. 30, 141-151.

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19. Omaye, S. T., N. I. Krinsky, V. E. Kagan, S. T. Mayne, D. C. Liebler and W. R. Bidlack (1997) Beta-carotene: friend or foe? Fundam. Appl. Toxicol. 40, 163-174.

20. Williams, A. W., T. W. Boileau, S. K. Clinton and J. W. Erdman Jr. (2000) [3-carotene stability and uptake by prostate cancer cells are dependent on delivery vehicle. Nutr. Cancer 36, 185190.

21. Junghans, A., H. Sies and W. Stahl (2000) Carotenoid-containing unilamellar liposomes loaded with glutathione: a model to study hydrophobic-hydrophilic antioxidant interaction. Free Radic. Res. 33, 801-808.

22. Woodall, A. A., G. Britton and M. J. Jackson (1997) Carotenoids and protection of phospholipids in solution or in liposomes against oxidation by peroxyl radicals: relationship between ca

rotenoid structure and protective ability. Biochim. Biophys. Acta 1336, 575-586.

23. Sujak, A., J. Gabrielska, W. Grudzinski, R. Broc, P. Mazurek and W. I. Gruszecki (1999) Lutein and zeaxanthin as protectors of lipid membranes against oxidative damage: the structural aspects. Arch. Biochem. Biophys. 371, 301-307.

24. Stahl, W., W. Schwarz, A. Sundquist and H. Sies (1992) Cistrans Isomers of lycopene and beta-carotene in human serum and tissue. Arch. Biochem. Biophys. 294, 173-177.

25. Paetau, I., D. Rao, E. R. Wiley, E. D. Brown and B. A. Clevidence (1999) Carotenoids in human buccal mucosa cells after

4 weeks of supplementation with tomato juice or lycopene supplements. Am. J. Clin. Nutr. 70, 490-494.

26. Burton, G. W. and K. U. Ingold (1984) Beta-carotene: an unusual type of lipid antioxidant. Science 224, 569-573.

27. Zhang, P. and S. T. Omaye (2001) Antioxidant and prooxidant roles for beta-carotene, alpha-tocopherol and ascorbic acid in human lung cells. Toxicol. In Vitro 15, 13-24.

28. Obermiller-Jevic, U. C., P. I. Francz, J. Frank, A. Flaccus and H. K. Biesalski (1999) Enhancement of the UVA induction of haem oxygenase-1 expression by beta-carotene in human skin fibroblasts. FEBS Left. 460, 212-216.

Olaf Eichler, Helmut Sies and Wilhelm Stahl*

Institut fur Physiologische Chemie I and Biologisch-Medizinisches Forschungszentrum, Heinrich-Heine-Universitat Dusseldorf, Dusseldorf, Germany

Received 16 October 2001; accepted 14 February 2002

Copyright American Society of Photobiology May 2002
Provided by ProQuest Information and Learning Company. All rights Reserved

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