Original Article

Journal of Investigative Dermatology (1986) 87, 348–353; doi:10.1111/1523-1747.ep12524446

Additive Effects of Ultraviolet B and Crude Coal Tar on Cutaneous Carcinogen Metabolism: Possible Relevance to the Tumorigenicity of the Goeckerman Regimen

Hasan Mukhtar1,2, Benjamin J DelTito Jr1,2, Peter M Matgouranis1,2, Mukul Das1,2, Parathasarathy Asokan1,2 and David R Bickers1,2

  1. 1Departments of Dermatology, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio, U.S.A.
  2. 2Veterans Administration Medical Center, Cleveland, Ohio, U.S.A.

Received 23 December 1985; Accepted 17 March 1986.

Top

Abstract

The effect of cutaneous exposure to ultraviolet B (UVB.) radiation alone, to crude coal tar (CCT) alone, and to the combination of UVB and CCT on the inducibility of the microsomal cytochrome P-450-dependent carcinogen- metabolizing enzyme aryl hydrocarbon hydroxylase (AHH) and other monooxygenases such as 7-ethoxyresorufin O-deethylase (ERD) and 7-ethoxycoumarin O-deethylase (ECD) activities in the skin of neonatal rats was studied. Exposure of the animals to UVB (400–1600 mJ/cm2) alone resulted in a dose-dependent increase in cutaneous enzyme activities. At a UVB dose of 1200 mJ/cm2 increases in AHH, ECD, and ERI) were 194%, 115%, and 244%, respectively. A single topical application of CCT (10 mI/kg) 24 h before sacrifice resulted in significant induction of AHH (350%), ECD) (921%), and ERD (796%) activities. Treatment of animals with the same dose of CCT followed by UVB exposure resulted in additive and/or synergistic effects on AHH (858%), ECD (1229%), and ERD (1166%) activities in tile skin. In contrast, exposure of animals to UVB prior to CCT application had effects no different from those of CCT alone. Epoxide hydrolase and glutathione S-transferase activities in skin from all experimental groups were not. different from those of controls High-pressure liquid chromatographic analysis of the metabolism of benzo[a]pyrene (BP) by cutaneous microsomes prepared from animals treated with UVB alone, CCT alone, and the combination of UVB and CCT revealed increased formation of all the metabolite in each experimental group. The largest increase in metabolite formation occurred in animals receiving CCT followed by UVB exposure. The inducibility of trans-7,8-dioI formation by UVB alone and CCT alone was 203% and 435%, respectively, whereas with CCT followed by UVB it was 1065%. The differential responses in AHH activity were found to parallel the capacity of skin microsomal enzymes to enhance the binding of [3H]-BP to DNA. These studies indicate that the sequence of exposure to the components of the Goeckerman regimen in rodents greatly influences matabolic activity in skin. When applied in the same sequence employed in the Goeckerman regimen (CCT followed by UVB exposure) the additive effect upon catalytic activity essential for cancer initiation suggests a possible mechanism for the enhancement of human skin cancer in individuals exposed to this therapeutic regimen.

Top

References

  1. Goeckerman, WH: Treatment of psoriasis: continued observations on the use of coal tar and ultraviolet light. Arch Dermatol 1931 24: 446–450,
  2. Emmett, EA: Ultraviolet radiation as a cause of skin tumors. CRC Crit Rev Toxicol 1973 2: 211–255,  | PubMed | ChemPort |
  3. Henry, SA: Occupational cutaneous cancer attributable to certain chemicals in industry. Br Med Bull 1947 4: 389–401,  | ISI | ChemPort |
  4. Stern, RS, Zierler, S, Parrish, JA: Skin carcinoma in patients with psoriasis treated with topical tar and artificial ultraviolet radiation. Lancet 1980 2: 732–733,  | PubMed |
  5. Epstein, JH: Risks and benefits of the treatment of psoriasis. N Engl J Med 1979 300: 852–853,  | PubMed | ChemPort |
  6. Stern, RS, Scotto, J, Fears, TR: Psoriasis and susceptibility to non-melanoma skin cancer. J Am Acad Dermatol 1985 12: 67–73,  | PubMed | ISI | ChemPort |
  7. Report on Coal Tar. National Institute for Occupational Safety and Health Publication, Washington, DC, 1977
  8. Rasmussen, JE: The crudeness of coal tar. Prog Dermatol 1978 12: 23–29,
  9. Kipling, DM: Soots, tars, and oils as causes of occupational cancer. Chemical Carcinogens 1976 Edited by CE Searle. Washington, DC, American Cancer Society, pp 315–323,
  10. Saperstein, MD, Wheeler, LA: Mutagenicity of coal tar preparations used in the treatment of psoriasis. Toxicol Lett 1979 3: 325–329,  | Article | ChemPort |
  11. Wheeler, LA, Saperstein, MD, Lowe, NJ: Mutagenicity of urine from psoriatic patients undergoing treatment with coal tar and ultraviolet light. J Invest Dermatol 1981 77: 181–185,  | Article | PubMed | ChemPort |
  12. Storer, JS, DeLeon, I, Millikan, LE, Laseter, JL, Griffing, C: Human absorption of crude coal tar products. Arch Dermatol 1984 120: 874–877,  | Article | PubMed | ChemPort |
  13. Conney, AH: Induction of microsomal enzymes by foreign chemicals and carcinogenesis by polycyclic aromatic hydrocarbons: GHA Clowes Memorial Lecture. Cancer Res 1982 42: 4875–4917,  | PubMed | ISI | ChemPort |
  14. Heidelberger, C: Chemical carcinogenesis. Annu Rev Biochem 1975 44: 79–121,  | Article | PubMed | ISI | ChemPort |
  15. Gelboin, HV: Benzo(a)pyrene metabolism, activation and carcinogenesis: role of regulation of mixed-function oxidases and related enzymes. Physiol Rev 1980 60: 1107–1166,  | PubMed | ISI | ChemPort |
  16. Bickers, DR, Dutta-Choudhury, T, Mukhtar, H: Epidermis: a site of drug metabolism in neonatal rat skin. Studies on cytochrome P-450 content and mixed function oxidase and epoxide hydrolase activity. Mol Pharmacol 1982 21: 239–247,  | PubMed | ISI | ChemPort |
  17. Mukhtar, H, Bickers, DR: Drug metabolism in skin: comparative activity of the mixed function oxidases, epoxide hydrolase, and glutathione-S-transferase in liver and skin of neonatal rat. Drug Metab Dispos 1981 9: 311–314,  | PubMed | ISI | ChemPort |
  18. Bickers, DR, Wroblewski, D, Choudhury, T, Mukhtar, H: Induction of neonatal rat skin and liver aryl hydrocarbon hydroxylase by coal tar and its constituents. J Invest Dermatol 1982 78: 227–229,  | Article | PubMed | ISI | ChemPort |
  19. Mukhtar, H, Link, CM, Cherniack, E, Kushner, DM, Bickers, DR: Effect of topical application of defined constituents of coal tar on skin and liver aryl hydrocarbon hydroxylase and 7-ethoxycoumarin deethylase activities. Toxicol Appl Pharmacol 1982 64: 541–549,  | Article | PubMed | ISI | ChemPort |
  20. Mukhtar, H, Bickers, DR: Evidence that coal tar is a mixed inducer of microsomal drug metabolizing enzymes. Toxicol Lett 1982 11: 221–227,  | Article | PubMed | ISI | ChemPort |
  21. Bickers, DR, Kappas, A: Human skin aryl hydrocarbon hydroxylase: induction by coal tar. J Clin Invest 1978 62: 1061–1068,  | PubMed | ISI | ChemPort |
  22. Merk, HF, Mukhtar, H, Bickers, DR: Human hair follicle: accessible tissue source for measuring enzyme-mediated DNA-binding of chemical carcinogens. Clin Res 1984 32: 482,
  23. Nebert, DW, Goujon, FM, Gielen, JE: Aryl hydrocarbon hydroxylase induction by polycyclic hydrocarbons—simple autosomal dominant trait in the mouse. Nature 1972 236: 107–110,  | ChemPort |
  24. Nebert, DW, Gelboin, HV: Substrate inducible microsomal aryl hydrocarbon hydroxylase in mammalian cell culture. I. Assay and properties of induced enzyme. J Biol Chem 1968 243: 6242–6249,  | PubMed | ISI | ChemPort |
  25. Greenlee, WF, Poland, A: An improved assay of 7-ethoxycoumarin O-deethylase activity: induction of hepatic enzyme activity in C57BL/6J and DBA/2J mice by phenobarbital, 3-methylcholanthrene, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. J Pharmacol Exp Ther 1978 205: 596–605,  | PubMed | ChemPort |
  26. Pohl, RJ, Fouts, JR: A rapid method for assaying the metabolism of 7-ethoxyresorufin by microsomal subcellular fractions. Anal Biochem 1980 107: 150–155,  | Article | PubMed | ChemPort |
  27. Asokan, P, Das, M, Rosenkranz, HS, Bickers, DR, Mukhtar, H: Topically applied nitropyrenes are potent inducers of cutaneous and hepatic monooxygenascs. Biochem Biophys Res Commun 1985 129: 134–140,  | Article | PubMed | ChemPort |
  28. Jerina, DM, Dansette, PM, Lu, AYH, Levin, W: Hepatic microsomal epoxide hydrase: a sensitive radiometric assay for hydration of arene oxides of carcinogenic aromatic hydrocarbons. Mol Pharmacol 1977 13: 342–351,  | PubMed | ChemPort |
  29. Lowry, OH, Rosebrough, NJ, Farr, AL, Randall, RJ: Protein measurement with the Polin phenol reagent. J Biol Chem 1951 193: 265–275,  | PubMed | ISI | ChemPort |
  30. Hesse, S, Jernstrom, B, Martinez, M, Moldeus, P, Christodoulides, L, Ketterer, B: Inactivation of DNA-binding metabolites of benzo(a)pyrene and benzo(a)pyrene-7,8-dihydrodiol by glutachione and glutathione-S-transferases. Carcinogenesis 1982 3: 757–760,  | PubMed | ChemPort |
  31. Lesca, P, Guenthner, TM, Oesch, F: Modulation of the covalent binding of aryl hydrocarbon metabolites to DNA in vitro after treatment of rats and mice with trans-stilbene oxide. Carcinogenesis 1981 2: 1049–1056,  | PubMed | ChemPort |
  32. Mukhtar, H, Del Tito, BJ Jr, Das, M, Cherniack, EP, Cherniack, AD, Bickers, DR: Clotrimazole, an inhibitor of epidermal benzo(a)pyrene metabolism and DNA binding and carcinogenicity of the hydrocarbon. Cancer Res 1984 44: 4233–4240,  | PubMed | ISI | ChemPort |
  33. Ashurst, SW, Cohen, GM: The formation of benzo(a)pyree-deoxy ribonucleoside adducts in vivo and in vitro. Carcinogenesis 1982 3: 267–273,  | PubMed | ChemPort |
  34. Bickers, DR, Mukhtar, H, Yang, SK: Cutaneous metabolism of benzo(a)pyrene: comparative studies in C57BL/6N and DBA/2N mice and neonatal Sprague-Dawley rats. Chem Biol Interact 1983 43: 263–270,  | PubMed | ChemPort |
  35. Unna, PG: The Histopathology of the Diseases of the Skin. Edinburgh, William FClay, 1896 p 719,
  36. Blum, HF: Carcinogenesis by Ultraviolet Light. Princeton, NJ, Princeton Univ Press, 1959
  37. Epstein, JH, Roth, HL: Experimental ultraviolet light Carcinogenesis. A study of croton oil promoting effects. J Invest Dermatol 1968 50: 387–400,  | PubMed | ChemPort |
  38. Tredger, JM, Chhabra, RS: Circadian variations in microsomal drug-metabolizing enzyme activities in rat and rabbit tissues. Xenobiotica 1977 7: 481–489,  | PubMed | ChemPort |
  39. Pohl, RJ, Fouts, JR: Xenobiotic metabolism in skin of hairless mice exposed to UV-radiation (UV), Aroclor 1260, or chlordane. Pharmacologist 1977 19: 200,
  40. Goerz, G, Merck, H, Bolsen, K, Tsambaos, D, Berger, H: Influence of UV-light exposure on hepatic and cutaneous monooxygenases. Experentia 1983 39: 385–386,  | Article | ChemPort |
  41. Bungeler, W: Uber den Einfluss photosensibilisierender Substantzen auf die Entstehung von Hautgeschwulston. Z Krebsforsch 1937 46: 130–132,  | ChemPort |
  42. Urbach, F: Modification of ultraviolet carcinogenesis by photoactive agents. J Invest Dermatol 1959 32: 373–378,  | PubMed | ChemPort |
  43. Findlay, GM: Ultraviolet light and skin cancer. Lancet 1928 2: 1070–1073,
  44. Morton, JJ, Luce-Clausen, EM, Mahoney, EB: Visible light and skin tumors induced with benzopyrene in mice. Cancer Res 1942 2: 256–260,  | ChemPort |
  45. Morton, JJ, Milder, GB, Luce-Clausen, EM, Mahoney, EB: The effect of visible light on the development in mice of skin tumors and leukemia induced by carcinogens. Cancer Res 1951 11: 559–561,  | PubMed | ISI | ChemPort |
  46. Rusch, HP, Kline, BE, Baumann, CA: The nonadditive effect of ultraviolet light and other carcinogenic procedures. Cancer Res 1942 2: 183–188,  | ChemPort |
  47. Maisin, J, Dejonghe, A: Au sujet de l'action de la lumiere et de l'ozone sur certains corps cancerigenes. C R Soc Biol (Paris) 1934 117: 114–119,
  48. Donaiach, I, Mottram, JC: On the effect of light on the incidence of tumors in painted mice. Am J Cancer 1940 39: 234–236,
  49. Kohn Speyer, AC: Effect of ultraviolet radiation on the incidence of tar cancer in mice. Lancet 1929 1: 1156–1157,
  50. Seelig, MG, Cooper, ZK: Light and tar cancer: an experimental study with a critical review of the literature on light as a carcinogenic factor. Surg Gynecol Obstet 1933 56: 752–761,

Extra navigation

.
ADVERTISEMENT