Summary
A comparative study of the antioxidant enzymes superoxide dismutase, catalase, glutathione reductase and thioredoxin reductase was undertaken in two families with xeroderma pigmentosum (XP) and in healthy controls of corresponding skin phototypes. Epidermal blister roofs obtained from the XP patients revealed significant decreases in catalase, thioredoxin reductase, and superoxide dismutase, but glutathione reductase was unaffected. In addition, keratinocytes established from XP patients contained a significantly higher than normal intracellular calcium concentration compared with control cells from a corresponding skin type. Keratinocytes established from an XP obligate heterozygote revealed intermediate levels of calcium between XP homozygotes and controls. Previously high intracellular calcium has been shown to compromise the redox status of keratinocytes by allosteric inhibition of the thioredoxin reductase/thioredoxin electron transfer system. In XP homozygous keratinocytes from sun-exposed epidermis, the intracellular concentration of reduced thioredoxin was decreased to 50% compared with these cells from unexposed skin. Taken together, the results from this study indicate that the epidermis in XP patients lacks effective defense against free radicals and peroxides. In addition to the well-established defect in the normal rates of unscheduled DNA repair, these findings provide an even better explanation for the multiple cutaneous neoplasms in these patients.
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References
Aronoff S (1965) Catalase: kinetics of photo-oxidation. Science 150:72–73
Athar M, Lloyd JR, Bickers DR, Mukhtar H (1989) Malignant conversion of UV-radiation and chemically induced mouse skin benign tumors by free-radical generating compounds. Carcinogenesis 10:1841–1845
Carraro C, Pathak MA (1988) Characterization of superoxide dismutase from mammalian skin epidermis. J Invest Dermatol 90:31–36
Chan GL, Little JB (1981) Gross sensitivity of certain xeroderma pigmentosum and cockayne syndrome fibroblast strains to both ionizing radiation and ultraviolet light. Mol Gen Genet 181:562–563
Chedekel M, Zeise L (1988) Sunlight, melanogenesis and radicals in skin lipids. Biophys J 23:587–591
Cleaver JE (1968) Defective repair replication of DNA in xeroderma pigmentosum. Nature 218:652–656
Cleaver JE (1968) Defective DNA repair in xeroderma pigmentosum. In: Upton AC, Albert RE, Burns FI, Shane DI (eds) Radiation carcinogenesis, Elsevier Science, New York, pp 43–55
DelRio LA, Ortega MG, Lopez AL, Gorge L (1977) A more sensitive modification of the catalase assay with the Clark oxygen electrode. Methods Enzymol 105:409–415
DeSimone RE, Penley MW, Charbonneau L, Smith SG, Wood JM, Hill HAO, Ridsdale S, Williams RJP (1973) The kinetics and mechanism for methyl and ethyl transfer to mercury. Biochim Biophys Acta 304:316–325
Fitzpatrick TB, Eisen AZ, Wolf K (1979) Dermatology in general medicine, 2nd edn. McGraw-Hill, New York, p 984
Flohe LF, Otting W (1984) Superoxide dismutase assays. Methods Enzymol 105:93–105
Fuchs J, Huflejt ME, Rothfuss LM, Wilson DS, Carcamo G, Packer L (1989) Acute effects of near ultraviolet and visible light on the cutaneous anti-oxidant defense system. Photochem Photobiol 50:739–744
Goth-Goldstein R (1977) Repair of DNA damage by alkylating carcinogens is defective in xeroderma pigmentosum fibroblasts. Nature 267:81–82
Jung EG (1986) Xeroderma pigmentosum. Int J Dermatol 25:629–633
Kalb VF Jr, Bernlohr RW (1977) A rapid method for protein determination. Anal Biochem 82:362–371
Kraemer KH, Slor H (1985) Xeroderma pigmentosum. Clin Dermatol 3:33–69
Luthman M, Holmgren A (1982) Rat liver thioredoxin and thioredoxin reductase purification and characterization. Biochemistry 21:6628–6633
Menon IA, Persad S, Ranadive NS, Haberman HF (1983) Formation of superoxide and cell damage during UV-irradiation of melanin. In: Bors W, Saran M, Tait D (eds) Oxygen radicals in chemistry and biology. W. de Gruyter, Berlin New York, pp 673–681
Parshad R, Sanford KK, Kraemer KH, Jones GM, Tarone RE (1990) Carrier detection in xeroderma pigmentosum. J Clin Invest 85:135–138
Pittelkow MR, Zinsmeister A, Steinmuller D (1983) Donor-recipient matching with the mixed lymphocyte-epidermal reaction. In: Gale RP (ed) Recent Advances in Bone Marrow Transplantation. Alan R. Liss, New York, pp 227–241
Rabilloud T, Asselineau D, Miguel C, Calvayrae R, Darmon M, Vuillaume M (1990) Deficiency in catalase activity correlates with the appearance of tumor phenotype in human keratinocytes. Int J Cancer 45:952–957
Rasheed A, El-Hafnawi H, Nagy G, Wiskemann A (1969) Elektronenmikroskopische Untersuchungen bei Xeroderma pigmentosum. Arch Klin Exp Dermatol 234:321–344
Regan JD, Setlow RB (1976) Repair of chemical damage in the DNA of human skin cells in culture. In Vitro 7:276–277
Ritter MA, Williams JR (1981) Fluorescent light induced lethality and DNA repair in normal and xeroderma pigmentosum fibroblasts. Biochim Biophys Acta 655:18–25
Robbins JH (1988) Xeroderma pigmentosum: defective DNA-repair causes skin cancer and neurodegeneration. JAMA 260:384–388
Sanford KK, Parshad R, Gantt R (1986) Responses of human cells in culture to hydrogen peroxide and related free radicals generated by visible light: relationship to cancer susceptibility. In: Johnson J (ed) Free radicals ageing and degenerative diseases, Alan R. Liss, New York, pp 373–394
Schallreuter KU, Pittelkow MR (1988) Defective calcium uptake in keratinocyte cell cultures from vitiliginous skin. Arch Dermatol Res 280:137–139
Schallreuter KU, Wood JM (1988) The activity and purification of membrane-associated thioredoxin reductase from human metastatic melanotic melanoma. Biochim Biophys Acta 967:103–109
Schallreuter KU, Wood JM (1989) Thioredoxin reductase in control of the pigmentary system. Clin Dermatol 7:92–105
Schallreuter KU, Wood JM (1989) Free radical reduction in the human epidermis. Free Radic Biol Med 6:519–532
Schallreuter KU, Hordinsky MK, Wood JM (1987) Thioredoxin reductase: role in free radical reduction in different hypopigmentation disorders. Arch Dermatol 123:615–619
Schallreuter KU, Pittelkow MR, Wood JM (1989) EF-hands calcium binding site regulates electron transfer for thioredoxin reductase/thioredoxin in human keratinocytes. Biochim Biophys Res Commun 162:1311–1316
Scott G (1985) Antioxidants in vitro and in vivo. Chem Britain: 648–653
Sundaram C, Köster W, Schallreuter KU (1990) The effect of UV-light and sun blockers on free radical defense in human and guinea pig epidermis. Arch Dermatol Res 282:526–531
Swift M, Chase C (1979) Cancer in families with xeroderma pigmentosum. J Natl Cancer Inst 62:1415–1420
Vuillaume M, Decroix Y, Calvayrae R, Vallot R, Best-Belpomme A (1983) Xeroderma pigmentosum: H2O2 formation and catalytic activity during the evolution of skin cells. CR Acad Sci (Paris) 845–850
Wood JM, Schallreuter KU (1988) Reduced thioredoxin inhibits melanin biosynthesis: evidence for the formation of a bis-cysteinate complex with tyrosinase. Inorganica Chim Acta 151:1
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Schallreuter, K.U., Pittelkow, M.R. & Wood, J.M. Defects in antioxidant defense and calcium transport in the epidermis of xeroderma pigmentosum patients. Arch Dermatol Res 283, 449–455 (1991). https://doi.org/10.1007/BF00371781
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DOI: https://doi.org/10.1007/BF00371781