Alterations in Benzo(a)Pyrene Metabolism and its DNA Adduct Formation in Skin of Mice Chronically Exposed to Ultraviolet-B Radiation

  • H. Mukhtar
  • M. Das
  • D. R. Bickers
Part of the NATO ASI Series book series (NSSA, volume 124)


Cutaneous xenobiotic metabolizing enzymes including aryl hydrocarbon hydroxylase (AHH), 7-ethoxycoumarin 0-deethylase (ECD), epoxide hydrolase (EH) and glutathione S-transferase (GST) activities were examined in SKH hairless mice chronically irradiated with UVB to induce squamous cell carcinoma (SCC). Enzyme activities in irradiated tumor-bearing skin were compared to those present in the skin of non-irradiated control animals as well as in unirradiated non-tumor bearing skin sites of the SCC-bearing mice. The inducibility of skin AHH and ECD in each set of animals was assessed following a single topical application of coal tar (1 ml/100 gm). Enzyme-mediated binding of 3H-benzo(a)pyrene (BP) and its metabolite 7β,8α-dihydroxy-9α,10α-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (BPDE-I) to epidermal DNA was also evaluated. Basal AHH and ECD activities in microsomes for UVB-irradiated SCC-bearing dorsal skin were 4.6 and 4.8-fold lower than those in dorsal skin of non-irradiated control animals. Enzyme activities in non-tumor bearing ventral skin from the UVB-irradiated SCC-bearing mice also were 2.2-2.8-fold lower as compared to activities in. the non-irradiated control animals. The reduction in AHH activity paralleled the levels of enzyme-mediated binding of radiolabeled BP metabolites and of BPDE-I to epidermal DNA. GST activity was found to be increased (173% in non-tumor bearing ventral skin of UVB-irradiated mice whereas no difference in activity between SCC-bearing dorsal skin and dorsal skin of sese control animals could be detected. EH activity was unchanged in each group of animals. Treatment with topically applied coal tar resulted in higher inducibility of AHH and ECU in both SCC-bearing (13-fold) as well as in non-tumor skin sites (6-fold) of UVB-irradiated mice than in skin of control animals (3-fold). Coal tar application also increased the covalent binding of 3H-BP and of the metabolite BPDE-I to skin DNA. This was greater in SCC-bearing dorsal skin (119–129%) than in non-irradiated skin of control animals (48–162%). Our studies suggest that the metabolism of BP by cutaneous cytochrome P-450 dependent monooxygenases is impaired in skin of mice irradiated chronically with UVB. These studies also illustrate the complex interrelationship that exist in target tissue simultaneously exposed to chemical and physical oncogens in the environment.


Covalent Binding Epoxide Hydrolase Dorsal Skin Hairless Mouse Aryl Hydrocarbon Hydroxylase 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



aryl hydrocarbon hydroxylase


epoxide hydrolase


7-ethoxycoumarin O-deethylase


glutathione S-transferase






5-oxide, benzo(a)pyrene 4,5-oxide


73,8α-dihydroxy-9α, 10 α-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene


ultraviolet B, CDNB, 1-chloro 2,4-dinitrobenzene


nicotinamide adenine dinucleotide reduced


nicotinamide adenine dinucleotide phosphate reduced


squamous cell carcinoma


polycyclic aromatic hydrocarbon


phosphate buffered saline


enzyme linked immunoabsorbent assay


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  1. 1.
    D. R. Bickers, in: “Current Concepts in Cutaneous Toxicity,” V. A. Drill and P. Lazar, eds, Academic Press, New York (1980), pp. 95–126.Google Scholar
  2. 2.
    E. A. Emmett, CRC Critical Rev. Toxicol. 2:211–255 (1973).CrossRefGoogle Scholar
  3. 3.
    G. M. Findlay, Lancet 24:1070–1073 (1928).CrossRefGoogle Scholar
  4. 4.
    R. K. Boutwell, in: “Carcinogenesis, A Comprehensive Survey, Vol. 2,” Raven Press, New York (1978), pp. 49–58.Google Scholar
  5. 5.
    A. H. Conney, Cancer Res. 42:4875–4917 (1982).PubMedGoogle Scholar
  6. 6.
    L. G. Sultatos and E. S. Vessell, Proc. Natl. Acad. Sci. USA 77:600–603 (1980).PubMedCrossRefGoogle Scholar
  7. 7.
    M. E. Mason and A. B. Okey, Cancer Res. 41:2778–2782 (1981).PubMedGoogle Scholar
  8. 8.
    D. W. Nebert, F. M. Goujon, and J. E. Gielen, Nature (Lond.) 236:107–110 (1972).Google Scholar
  9. 9.
    L. G. Hart, R. H. Adamson, H. P. Morris, and J. R. Fouts, J. Pharmacol. Exp. Ther. 149:7–15 (1965).PubMedGoogle Scholar
  10. 10.
    R. H. Adamson and J. R. Fouts, Cancer Res. 21:667–672 (1961).Google Scholar
  11. 11.
    H. P. Morris, H. Sidransky, B. P. Wagner, and H. M. Dyer, Cancer Res. 20:1252–1254 (1960).PubMedGoogle Scholar
  12. 12.
    H. Mukhtar and D. R. Bickers, Drug Metab. Disp. 9:311–314 (1981).Google Scholar
  13. 13.
    H. Mukhtar, B. J. Del Tito, Jr., M. Das, E. P. Cherniack, E. A. Cherniack, and D. R. Bickers, Cancer Res. 44:4233–4240 (1984).PubMedGoogle Scholar
  14. 14.
    R. Santella, C. D. Lin, W. L. Cleveland, and I. B. Weinstein, Carcinogenesis 5:373–378 (1984).PubMedCrossRefGoogle Scholar
  15. 15.
    W. H. Habig, M. J. Pabst, and W. B. Jakoby, J. Biol. Chem. 249:7130–7139 (1974).PubMedGoogle Scholar
  16. 16.
    O. H. Lowry, N. J. Rosebrough, A. L. Farr, and R. J. Randall, J. Biol. Chem. 193:265–275 (1951).PubMedGoogle Scholar
  17. 17.
    Y. Miyake, J. L. Gaylor, and H. P. Morris, J. Biol. Chem. 249:1980–1987 (1974).PubMedGoogle Scholar
  18. 18.
    H. Mukhtar, C. M. Link, E. Cherniack, A. M. Kushner, and D. R. Bickers, Toxicol. Appl. Pharmacol. 64:541–549 (1982).PubMedCrossRefGoogle Scholar
  19. 19.
    G. A. LePage and J. F. Henderson, in: “Progress in Experimental Tumor Research, Vol. 1 ” Kargar, Basel/New York, (1960) pp. 440–476.Google Scholar
  20. 20.
    V. R. Potter, Cancer Res. 21:1331–1333 (1961).PubMedGoogle Scholar
  21. 21.
    G. Hodgson, Brit. J. Dermatol. 60:282–284 (1948).CrossRefGoogle Scholar
  22. 22.
    S. A. Henry, Brit. Med. Bull; 4:389–401 (1947).PubMedGoogle Scholar
  23. 23.
    W. E. Poel and A. G. Kammer, J. Natl. Cancer Inst. 18:41–55 (1957).PubMedGoogle Scholar
  24. 24.
    G. Kellerman, G. R. Shaw, and N. Luyten-Kellerman, N. Engl. J. Med. 289:934–937 (1972).CrossRefGoogle Scholar
  25. 25.
    J. H. Epstein, F. J. Sullivan, and W. L. Epstein, J. Invest. Dermatol. 36:73–77 (1961).PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1986

Authors and Affiliations

  • H. Mukhtar
    • 1
    • 2
  • M. Das
    • 1
    • 2
  • D. R. Bickers
    • 1
    • 2
  1. 1.Department of DermatologyUniversity Hospitals of Cleveland Case Western Reserve UniversityClevelandUSA
  2. 2.Veterans Administration Medical CenterClevelandUSA

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