Comprehensive Physiology Wiley Online Library

Cutaneous Carcinogenesis: Metabolic Interaction of Chemical Carcinogens with Skin

Full Article on Wiley Online Library


The sections in this article are:

1 Initiation
1.1 Initiating Agents
1.2 Metabolic Response to Chemical Carcinogens
1.3 Aryl Hydrocarbon Hydroxylases
1.4 Role of Cutaneous Aryl Hydrocarbon Hydroxylase in Tumorigenesis
1.5 Conjugases
2 Role of the Pilosebaceous Apparatus in Initiation
2.1 Interaction of Chemical Carcinogens with Cells
3 Promotion
3.1 Modification of the Initial Carcinogen‐Cell Interaction
3.2 Later Stages of Promotion
4 Photochemical Carcinogenesis
5 Conclusion
Figure 1. Figure 1.

Kinetics of aryl hydrocarbon hydroxylase induction in mouse skin 202. Various amounts of benz[a]anthracene in 0.2 ml of acetone were applied to the shaven skin of Swiss mice and enzyme activity (pmole of phenolic product/mg protein/30 min) was determined in homogenates at various times after application as described by Gelboin and co‐workers 61.

Figure 1.

Kinetics of aryl hydrocarbon hydroxylase induction in mouse skin 202. Various amounts of benz[a]anthracene in 0.2 ml of acetone were applied to the shaven skin of Swiss mice and enzyme activity (pmole of phenolic product/mg protein/30 min) was determined in homogenates at various times after application as described by Gelboin and co‐workers 61.

 1. Abell, C. W., and C. Heidelberger. Interaction of carcinogenic hydrocarbons with tissues. VIII. Binding of tritiumlabeled hydrocarbons to the soluble proteins of mouse skin. Cancer Res. 22: 931–946, 1962.
 2. Ahlstrom, C. G., and N. O. Berg. Fluorescence analysis of the histological localization of 3,4‐benzpyrene in mouse skin with special regard to variations between different areas of the skin. Acta Pathol. Microbiol. Scand. 14: 283–298, 1947.
 3. Allison, A. C. Lysosomes in relation to cancer induction and treatment. Europ. J. Cancer 3: 481–490, 1968.
 4. Alvares, A. P., A. Kappas, W. Levin, and A. H. Conney. Inducibility of benzo(a)pyrene hydroxylase in human skin by polycyclic hydrocarbons. Clin. Pharmacol. Therap. 14: 30–40, 1973.
 5. Bates, R. R., J. S. Wortham, W. B. Counts, C. W. Dingman, and H. V. Gelboin. Inhibition of actinomycin D of DNA synthesis and skin tumorigenesis induced by 7,12‐dimethylbenz(a)anthracene. Cancer Res. 28: 27–34, 1968.
 6. Benedict, W. F., N. Considine, and D. W. Nebert. Genetic differences in aryl hydrocarbon hydroxylase induction and benzo(a)pyrene‐produced tumorigenesis in the mouse. Mol. Pharmacol. 6: 266–277, 1973.
 7. Berenblum, I. The cocarcinogenic action of croton resin. Cancer Res. 1: 44–48, 1941.
 8. Berenblum, I., and P. Shubik. The role of croton oil applications, associated with a single painting of carcinogen, in tumour induction of the mouse's skin. Brit. J. Cancer 1: 379–382, 1947.
 9. Bickers, D. R., A. Kappas, and A. P. Alvares. Differences in inducibility of cutaneous and hepatic drug metabolizing enzymes and cytochrome P‐450 by polychlorinated biphenyls and 1,1,1‐trichloro‐2,2‐bis (p‐chlorophenyl) ethane (DDT). J. Pharm. Exptl. Therap. 118: 300–309, 1974.
 10. Blum, H. F. Carcinogenesis by ultraviolet light. Princeton, New Jersey: Princeton Univ. Press, 1959, p. 1–340.
 11. Bock, F. G. Early effects of hydrocarbons on mammalian skin. Progr. Exptl. Tumor Res. 4: 126–168, 1964.
 12. Bock, F. G., and R. Mund. A survey of compounds for activity in the suppression of mouse sebaceous glands. Cancer Res. 18: 887–892, 1958.
 13. Bowden, G. T., T. J. Slaga, B. G. Shapas, and R. K. Boutwell. The role of aryl hydrocarbon hydroxylase in skin tumor initiation by 7,12‐dimethylbenz[a]anthracene and 1,2,5,6‐dibenzanthracene using DNA binding and thymidine‐3H incorporation into DNA as criteria. Cancer Res. 34: 2634–2642, 1974.
 14. Boyland, E., and B. Green. The interaction of polycyclic hydrocarbons and nucleic acids. Brit. J. Cancer 16: 507–517, 1962.
 15. Boyland, E., and K. Williams. An enzyme catalyzing the conjugation of epoxides with glutathione. Biochem. J. 94: 190–197, 1965.
 16. Brand, K. G., L. C. Buoen, and I. Brand. Carcinogenesis from polymer implants: new aspects from chromosomal and transplantation studies during premalignancy. J. Natl. Cancer Inst. 39: 663–679, 1967.
 17. Brookes, P., and P. D. Lawley. Reaction of some mutagenic and carcinogenic compounds with nucleic acids. J. Cell. Comp. Physiol. 64: 111–120, 1964.
 18. Bürki, K., A. G. Liebelt, and E. Bresnick. Induction of aryl hydrocarbon hydroxylase in mouse tissues from a high and low cancer strain and their F1 hybrids. J. Natl. Cancer Inst. 50: 369–380, 1973.
 19. Bürki, K., A. G. Liebelt, and E. Bresnick. Expression of aryl hydrocarbon hydroxylase induction in mouse tissues in vivo and in organ culture. Arch. Biochem. Biophys. 158: 641–649, 1973.
 20. Bürki, K., J. E. Wheeler, Y. Akamatsu, J. E. Scribner, G. Candelas, and E. Bresnick. Early differential effects of 3‐methylcholanthrene and its “K‐region” epoxide on mouse skin; possible implication in the two‐stage mechanism of tumorigenesis. J. Natl. Cancer. Inst. 53: 967–976, 1974.
 21. Calcutt, G. Sulfyhydryl groups and tumor induction by chemical agents. Brit. J. Cancer 15: 673–682, 1961.
 22. Campbell, T. C., and J. R. Hayes. Role of nutrition in the drug‐metabolizing enzyme system. Pharmacol. Rev. 26: 171–197, 1974.
 23. Cavalieri, E., and M. Calvin. Photochemical coupling of benzo(a)pyrene with 1‐methylcytosine; photoenhancement of carcinogenicity. Photochem. Photobiol. 14: 641–653, 1971.
 24. Chan, P. C., T. Okamoto, and E. L. Wynder. The possible role of riboflavin deficiency in epithelial neoplasia. III. Induction of microsomal aryl hydrocarbon hydroxylase. J. Natl. Cancer Inst. 48: 1341–1345, 1972.
 25. Chasseaud, L. F. The nature and distribution of enzymes catalyzing the conjugation of glutathione with foreign compounds. Drug Metab. Rev. 2: 185–220, 1973.
 26. Clayson, D. B. Chemical Carcinogenesis. Boston: Little, Brown, 1962, p. 1–467.
 27. Cleaver, J. E. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218: 652–656, 1968.
 28. Cleaver, J. E. DNA repair with purines and pyrimidines in radiation‐ and carcinogen‐damaged normal and xeroderma pigmentosum human cells. Cancer Res. 33: 362–369, 1973.
 29. Clendenning, W. Xeroderma pigmentosum. In: Dermatology in General Medicine, edited by T. B. Fitzpatrick, K. Arndt, W. Clark, A. Z. Eisen, E. J. Van Scott, and J. H. Vaughan. New York: McGraw‐Hill, 1971, p. 436–439.
 30. Colburn, N. H., and R. K. Boutwell. The in vivo binding of β‐propiolactone to mouse skin DNA, RNA, and protein. Cancer Res. 28: 642–652, 1968.
 31. Colburn, N. H., and R. K. Boutwell. The binding of β‐propiolactone and some related alkylating agents to DNA, RNA, and protein of mouse skin: relation between tumorinitiating power of alkylating agents and their binding to DNA. Cancer Res. 28: 653–660, 1968.
 32. Conney, A. H. Pharmacological implication of microsomal enzyme induction. Pharmacol. Rev. 19: 317–366, 1967.
 33. Conney, A. H., and J. J. Burns. Metabolic interactions among environmental chemicals and drugs. Science 178: 576–586, 1972.
 34. Conney, A. H., E. C. Miller, and J. A. Miller. Substrateinduced synthesis and other properties of benzpyrene hydroxylase in rat liver. J. Biol. Chem. 228: 753–766, 1957.
 35. Crabtree, H. G. Influence of bromobenzene on the induction of skin tumors by 3,4‐benzpyrene. Cancer Res. 4: 688–693, 1944.
 36. Crabtree, H. G. Influence of unsaturated dibasic acids on the induction of skin tumors by chemical carcinogens. Cancer Res. 5: 346–351, 1945.
 37. Crabtree, H. G. Some effects of aromatic hydrocarbons on sulfur metabolism and tumor induction in mice. Cancer Res. 6: 553–559, 1946.
 38. Crabtree, H. G. Anti‐carcinogenesis. Brit. Med. Bull. 4: 345–348, 1947.
 39. Cruickshank, C. N. D., and J. R. Squire. Skin cancer in the engineering industry from use of mineral oil. Brit. J. Indust. Med. 7: 1–3, 1950.
 40. Diamond, L., and H. V. Gelboin. Alpha‐naphthoflavone: An inhibitor of hydrocarbon cytotoxicity and microsomal hydroxylase. Science 166: 1023–1025, 1969.
 41. Diengdoh, J. V. Lysosomes in malignant skin tumours. Nature, London 215: 861–862, 1967.
 42. Dingman, C. W., and M. B. Sporn. The binding of metabolites of aminoazo dyes to rat liver DNA in vivo. Cancer Res. 27: 938–944, 1967.
 43. DiPaolo, J. A. Skin‐SH levels of mice. Nature 198: 1007–1008, 1963.
 44. DiPaolo, J. A., and T. F. Niedbala. Amperometric determination of sulfhydryl changes in mouse epidermis and dermis during treatment with certain polycyclic hydrocarbons. Proc. Soc. Exptl. Biol. Med. 96: 255–259, 1957.
 45. Doniach, I., and J. C. Mottram. On the effect of light upon the incidence of tumors in painted mice. Am. J. Cancer 39: 234–240, 1940.
 46. Dutton, G. J., and I. H. Stevenson. The stimulation by 3,4‐benzpyrene of glucuronide synthesis in skin. Biochim. Biophys. Acta 58: 633–634, 1962.
 47. Epstein, J. H. Ultraviolet carcinogenesis. Photophysiology 5: 235–273, 1970.
 48. Epstein, J. H., and W. L. Epstein. Cocarcinogenic effect of ultraviolet light on DMBA tumor initiation in albino mice. J. Invest. Dermatol. 39: 455–460, 1962.
 49. Epstein, J. H., K. Fukuyama, W. B. Reed, and W. L. Epstein. Defect in DNA synthesis in skin of patients with xeroderma pigmentosum demonstrated in vivo. Science 168: 1477–1478, 1970.
 50. Epstein, J. H., and H. L. Roth. Experimental ultraviolet light carcinogenesis. A study of croton oil promoting effects. J. Invest. Derm. 50: 387–389, 1968.
 51. Farber, E. Carcinogenesis‐cellular evolution as a unifying thread: Presidential address. Cancer Res. 33: 2537–2550, 1973.
 52. Fjellstedt, T. A., R. H. Allen, B. K. Duncan, and W. B. Jakoby. Enzymatic conjugation of epoxides with glutathione. J. Biol. Chem. 248: 3702–3707, 1973.
 53. Frei, J. V., and A. C. Ritchie. Diurnal variation in the susceptibility of mouse epidermis to carcinogen and its relationship to DNA synthesis. J. Natl. Cancer Inst. 32: 1213–1220, 1964.
 54. Friedewald, W. F., and P. Rous. The initiating and promoting elements in tumor production. An analysis of the effects of tar, benzpyrene, and methylcholanthrene on rabbit skin. J. Exptl. Med. 80: 101–125, 1944.
 55. Gelboin, H. V. A microsome‐dependent binding of benzo(a)pyrene to DNA. Cancer Res. 29: 1272–1276, 1969.
 56. Gelboin, H. V. Carcinogens, enzyme induction, and gene action. Advan. Cancer Res. 10: 1–81, 1967.
 57. Gelboin, H. V., M. Klein, and R. R. Bates. Inhibition of mouse skin tumorigenesis by actinomycin D. Proc. Natl. Acad. Sci. 53: 1353–1360, 1965.
 58. Gelboin, H. V., E. Huberman, and L. Sachs. Enzymatic hydroxylation of benzopyrene and its relationship to cytotoxicity. Proc. Natl. Acad. Sci. 64: 1188–1194, 1969.
 59. Gelboin, H. V., N. Kinoshita, and F. J. Wiebel. Microsomal hydroxylases: induction and role in polycyclic hydrocarbon carcinogenesis and toxicity. Federation Proc. 31: 1298–1309, 1972.
 60. Gelboin, H. V., M. Klein, and R. R. Bates. Inhibition of mouse skin tumorigenesis by actinomycin D. Proc. Natl. Acad. Sci. 53: 1353–1360, 1965.
 61. Gelboin, H. V., F. J. Wiebel, and L. Diamond. Dimethyl‐benzanthracene tumorigenesis and aryl hydrocarbon hydroxylase in mouse skin: inhibition by 7,8‐benzoflavone. Science 170: 169–171, 1970.
 62. Gielen, J. E., F. M. Goujon, and D. W. Nebert. Genetic regulation of aryl hydrocarbon hydroxylase induction. II. Simple Mendelian expression in mouse tissues in vivo. J. Biol. Chem. 247: 1125–1137, 1972.
 63. Gillette, J. R., D. C. Davis, and H. A. Sasame. Cytochrome P‐450 and its role in drug metabolism. Ann. Rev. Pharmacol. 12: 57–84, 1972.
 64. Giovanella, B. C., and C. Heidelberger. Studies on the role of the hair follicle in epidermal carcinogenesis (Abstract). Proc. Am. Assoc. Cancer Res. 8: 21, 1967.
 65. Giovanella, B. C., J. Liegel, and C. Heidelberger. The refractoriness of the skin of hairless mice to chemical carcinogenesis. Cancer Res. 30: 2590–2597, 1970.
 66. Goshman, L. M., and C. Heidelberger. Binding of tritiumlabeled polycyclic hydrocarbons to DNA of mouse skin. Cancer Res. 27: 1678–1688, 1967.
 67. Graffi, A. Untersuchungen zur Frage der Bedeutung der Mitochondrien bei der Kanzerisierung. Dtsch. Gesundh Wes. 49: 2305–2312, 1967.
 68. Graffi, A., F. Scharsach, and E. Heyer. Zur Frage der Initialwirkung cancerogener Kohlenwasserstoffe auf die Mäusehaut nach intravenöser, intraperitonealer und oraler Applikation. Naturwissenschaften 42: 184, 1955.
 69. Griffin, A. C. Methoxsalen in ultraviolet carcinogenesis in the mouse. J. Invest. Derm. 32: 367–372, 1959.
 70. Grover, P. L., A. Hewer, and P. Sims. Epoxides as microsomal metabolites of polycyclic hydrocarbons. FEBS Letters 18: 76–80, 1971.
 71. Grover, P. L., and P. Sims. Enzyme‐catalyzed reactions of polycyclic hydrocarbons with deoxyribonucleic acid and protein in vitro. Biochem. J. 110: 159–160, 1968.
 72. Guldberg, G. Experimental researches on precancerous changes in the skin and skin cancer. Acta Pathol. Microbiol. Scand., Suppl. 8: 1–192, 1931.
 73. Halprin, K. M., and A. Ohkawara. The measurement of glutathione in human epidermis using glutathione reductase. J. Invest. Derm. 48: 149–152, 1967.
 74. Haran, N., and I. Berenblum. The induction of the initiating phase of skin carcinogenesis in the mouse by oral administration of urethane (ethyl carbamate). Brit. J. Cancer 10: 57–60, 1956.
 75. Harper, K. H., and G. Calcutt. Conjugation of 3,4‐benzpyrenols in mouse skin. Nature 186: 80–81, 1960.
 76. Hartwell, J. L. Survey of compounds which have been tested for carcinogenic activity. Washington D.C.: U. S. Govt. Printing Office, 1949.
 77. Hecker, E. Cocarcinogenic principles from the seed oil of Croton tiglium and from other Euphorbiaceae. Cancer Res. 28: 2338–2349, 1968.
 78. Heidelberger, C. Studies on the cellular and molecular mechanism of hydrocarbon carcinogenesis. Europ. J. Cancer 6: 161–172, 1970.
 79. Heidelberger, C., and M. G. Moldenhauer. The interaction of carcinogenic hydrocarbons with tissue constituents. IV. A quantitative study of the binding to skin proteins of several 14C‐labeled hydrocarbons. Cancer Res. 16: 442–449, 1956.
 80. Heller, W. Experimentelle Untersuchungen über den Lichtkrebs. II. Mitteilung: Lichtkrebserzeugung durch Photosensibilisierung. Strahlentherapie 81: 529, 1950.
 81. Hennings, H., D. Michael, and E. Patterson. Enhancement of skin tumorigenesis by a single application of croton oil before or soon after initiation by urethan. Cancer Res. 33: 3130–3134, 1973.
 82. Hennings, H., G. T. Bowden, and R. K. Boutwell. The effect of croton oil pretreatment on skin tumor initiation in mice. Cancer Res. 29: 1773–1780, 1969.
 83. Hiraki, S. Carcinogenic effect on N,N′‐dimethylnitrosourea on Syrian hamsters. Gann 62: 321–323, 1971.
 84. Hodgson, G. A., and H. J. Whiteley. Personal susceptibility to pitch. Brit. J. Ind. Med. 27: 160–166, 1970.
 85. Hueper, W. C., and W. D. Conway. Chemical carcinogenesis and cancers. American Lecture Series, edited by I. N. Kugelmass, Springfield, III.: Thomas, 1964.
 86. Huggins, C., L. Grand, and R. Fukunishi. Aromatic influences on the yields of mammary cancers following administration of 7,12‐dimethylbenz(a)anthracene. Proc. Natl. Acad. Sci. 51: 737–742, 1964.
 87. Irving, C. C. Conjugates of N‐Hydroxy compounds. In: Metabolic conjugation and metabolic hydrolysis, vol. 1, edited by W. H. Fishman. New York: Academic, 1970, p. 53–119.
 88. Irving, C. C., D. H. Janss, and L. T. Russell. Lack of N‐Hydroxy‐2‐acetylaminofluorene sulfotransferase activity in the mammary gland and Zymbal's gland of the rat. Cancer Res. 31: 387–391, 1971.
 89. Iversen, O., and A. Evensen. Experimental skin carcinogenesis in mice. Acta Path. Microbiol. Scand., Suppl. 156: 1–184, 1962.
 90. Jacobs, A. J., R. L. O'Brien, J. W. Parker, and P. Paolilli. Abnormal DNA repair of 4‐nitroquinoline‐1‐oxide‐induced damage by lymphocytes in Xeroderma pigmentosum. Mutat. Res. 16: 420–424, 1972.
 91. Jacquier, A., and P. Daudel. Sur L'Interaction in vivo du 3:4‐Benzopyrene et de L'Acide Desoxyribonucleique de la Peau de Souris. Compt. Rend. 258: 5775–5776, 1964.
 92. Jerina, D. M., J. W. Daly, B. Witkop, P. Zaltzman‐Nirenberg, and S. Udenfriend. 1,2‐Naphthalene oxide as an intermediate in the microsomal hydroxylation of naphthalene. Biochemistry 9: 147–156, 1970.
 93. Jerina, D. M., N. Kaubisch, and J. W. Daly. Arene oxides as intermediates in the metabolism of aromatic substrates: alkyl and oxygen migrations during isomerization of alkylated arene oxides. Proc. Natl. Acad. Sci. 68: 2545–2548, 1971.
 94. Jollow, D. J., J. R. Mitchell, N. Zampaglione, and J. R. Gillette. Bromobenzene induced liver necrosis. Protective role of glutathione and evidence for 3,4‐bromobenzene‐oxide as the hepatotoxic metabolite. Pharmacology 11: 151–169, 1974.
 95. Khan, A. U., and M. Kasha. An optical‐residue singletoxygen theory of photo carcinogenicity. Ann. NY Acad. Sci. 171: 24–32, 1970.
 96. Kinoshita, N., and H. V. Gelboin. Aryl hydrocarbon hydroxylase and polycyclic hydrocarbon tumorigenesis: effect of the enzyme inhibitor 7,8‐benzoflavone on tumorigenesis and macromolecule binding. Proc. Natl. Acad. Sci. 69: 824–828, 1972.
 97. Kinoshita, N., and H. V. Gelboin. The role of aryl hydrocarbon hydroxylase in 7,12‐dimethylbenz(a)anthracene skin tumorigenesis: on the mechanism of 7,8‐benzoflavone inhibition of tumorigenesis. Cancer Res. 32: 1329–1339, 1972.
 98. Klein, M. Inhibition of skin tumorigenesis in strain B6AF1/J. female mice with maleic anhydride. J. Natl. Cancer Inst. 34: 175–183, 1965.
 99. Kodama, Y., and F. G. Bock. Benz(a)pyrene‐metabolizing enzyme activity of livers of various strains of mice. Cancer Res. 30: 1846–1849, 1970.
 100. Kuntzman, R., M. Jacobson, K. Schneidman, and A. H. Conney. Similarities between oxidative drug metabolizing enzymes and steroid hydroxylases in liver microsomes. J. Pharmacol. Exptl. Therap. 146: 280–285, 1964.
 101. Kouri, R. E., R. A. Salerno, and C. E. Whitmire. Relationships between aryl hydrocarbon hydroxylase inducibility and sensitivity to chemically induced subcutaneous sarcomas in various strains of mice. J. Natl. Cancer Inst. 50: 363–368, 1973.
 102. Krauch, C. H., D. M. Kraemer, and A. Wacker. Zum Wirkungsmechanismus photodynamischer Furocumarine. Photoreaktion von Psoralen‐(4‐14C) mit DNS, RNS, Homopoylynucleotiden und Nucleosiden. Photochem. Photobiol. 6: 341–354, 1967.
 103. Laerum, O. D., and O. H. Iversen. Reticuloses and epidermal tumors in hairless mice after topical skin applications of cantharidin and asiaticoside. Cancer Res. 32, 1463–1469, 1972.
 104. Lappe, M. A. Tumor specific transplantation antigens: possible origin in premalignant lesions. Nature 223: 82–84, 1969.
 105. Law, L. W. Studies of the significance of tumor antigens in induction and repression of neoplastic diseases: presidential address. Cancer Res. 29: 1–21, 1969.
 106. Levin, W., A. H. Conney, A. P. Alvares, I. Merkatz, and A. Kappas. Induction of benzo(a)pyrene hydroxylase in human skin. Science 28: 419–420, 1972.
 107. Lewis, M. R. The photosensitivity of chick‐embryo cells growing in media containing certain carcinogenic substances. Am. J. Cancer 25: 305–309, 1935.
 108. Lieberman, M. W., and M. C. Poirier. Deoxyribonucleoside incorporation during DNA repair of carcinogen‐induced damage in human diploid fibroblasts. Cancer Res. 33: 2097–2103, 1973.
 109. Major, I. R. Correlation of initial changes in the mouse epidermal cell population with two stage carcinogenesis‐a quantitative study. Brit. J. Cancer 24: 149–163, 1970.
 110. McKenzie, I., and P. Rous. The experimental disclosure of latent neoplastic changes in tarred skin. J. Exptl. Med. 73: 391–416, 1941.
 111. Miller, E. C. Studies on the formation of protein bound derivatives of 3,4‐benzpyrene in the skin of mice. Cancer Res. 10: 232, 1950.
 112. Miller, J. A. Carcinogenesis by chemicals: An overview ‐ G. H. A. Clowes Memorial Lecture. Cancer Res. 30: 559–576, 1970.
 113. Miller, E. C., and J. A. Miller. In vivo combinations between carcinogens and tissue constituents and their possible role in carcinogenesis. Cancer Res. 12: 547–556, 1952.
 114. Montgomery, H. Dermatopathology. New York: Harper & Row, 1967, p. 123–127.
 115. Morton, J. J., E. M. Luce‐Clausen, and E. B. Mahoney. Visible light and skin tumors induced with benzpyrene in mice. Cancer Res. 2: 256–260, 1942.
 116. Muller, H. K., and R. C. Sutherland. Epidermal antigens in cutaneous dysplasia and neoplasia. Nature, London 230: 384–385, 1971.
 117. Nakahara, W., F. Fukuoka, and T. Sugimura. Carcinogen action of 4‐nitroquinoline‐N‐oxide. Gann 48: 129–137, 1957.
 118. Nebert, D. W., L. L. Bausserman, and R. R. Bates. Effect of 17‐β‐estradiol and testosterone on aryl hydrocarbon hydroxylase activity in mouse tissues in vivo and in cell culture. Intern. J. Cancer 6: 470–480, 1970.
 119. Nebert, D. W., W. F. Benedict, J. E. Gielen, F. Oesch, and J. W. Daly. Aryl hydrocarbon hydroxylase, epoxide hydrase, and 7,12‐dimethylbenz(a)anthracene‐produced skin tumorigenesis in the mouse. Mol. Pharmacol. 8: 374–379, 1972.
 120. Nebert, D. W., and H. V. Gelboin. The in vivo and in vitro induction of aryl hydrocarbon hydroxylase in mammalian cells of different species, tissues, strains, and developmental and hormonal states. Arch. Biochem. Biophys. 134: 76–89, 1969.
 121. Nebert, D. W., and H. V. Gelboin. Substrate‐inducible microsomal aryl hydroxylase in mammalian cell culture. I. Assay and properties of induced enzyme. J. Biol. Chem. 243: 6242–6249, 1968.
 122. Nebert, D. W., and H. V. Gelboin. Substrate‐inducible microsomal aryl hydroxylase in mammalian cell culture. II. Cellular responses during enzyme induction. J. Biol. Chem. 243: 6250–6261, 1968.
 123. Nebert, D. W., and H. V. Gelboin. The role of ribonucleic acid and protein synthesis in microsomal aryl hydrocarbon hydroxylase induction in cell culture. J. Biol. Chem. 245: 160–168, 1970.
 124. Nebert, D. W., F. M. Goujon, and J. E. Gielen. Aryl hydrocarbon hydroxylase induction by polycyclic hydrocarbons: Simple autosomal dominant trait in the mouse. Nature New Biol., London 236: 107–110, 1972.
 125. Neubauer, O. Arsenical Cancer: a review. Brit. J. Cancer 1: 192–251, 1947.
 126. Oesch, F. Mammalian expoxide hydrases: inducible enzymes catalysing the inactivation of carcinogenic and cytotoxic metabolites derived from aromatic and olefinic compounds. Xenobiotica 3: 305–340, 1972.
 127. Oesch, F., and J. Daly. Conversion of naphthalene to trans‐naphthalene dihydrodiol: evidence for the presence of a coupled aryl monoxygenase‐epoxide hydrase system in hepatic microsomes. Biochem. Biophys. Res. Comm. 46: 1713–1720, 1972.
 128. Oesch, F., N. Kaubisch, D. M. Jerina, and J. W. Daly. Hepatic epoxide hydrase. Structure‐activity relationships for substrates and inhibitors. Biochemistry 10: 4858–4866, 1971.
 129. Parish, D. J., and C. E. Searle. The carcinogenicity of β‐propiolactone and 4‐nitroquinoline‐N‐oxide for the skin of the golden hamster. Brit. J. Cancer 20: 206–209, 1966.
 130. Pitot, H. C., and Y. S. Cho. Control mechanisms in the normal and neoplastic cell. Progr. Exptl. Tumor Res. 7: 158–223, 1965.
 131. Pitot, H. C., and C. Heidelberger. Metabolic regulatory circuits and carcinogenesis. Cancer Res. 23: 1694–1700, 1963.
 132. Pliss, G. B., and M. A. Zabezhinsky. Carcinogenic properties of orthotolidine (3,3‐dimethylbenzidine). J. Natl. Cancer Inst. 45: 283–295, 1970.
 133. Pott, P. Chirurgical observations relative to the cancer of the scrotum. London, 1775. Reprinted in Natl. Cancer Inst. Monograph 10: 7–13, 1963.
 134. Pound, A. W. Further observations concerning the influence of preliminary stimulation by croton oil and acetic acid on the initiation of skin tumours in mice by urethane. Brit. J. Cancer 20: 385–398, 1966.
 135. Pound, A. W. Carcinogenesis and cell proliferation. New Zealand Med. J. 67: 88–99, 1968.
 136. Pound, A. W. Tumour formation in mice by urethane administered with related carbamates. Brit. J. Cancer 26: 216–225, 1972.
 137. Prehn, R. T. Immunosurveillance, regeneration and oncogenesis. Progr. Exptl. Tumor Res. 14: 1–24, 1971.
 138. Purchase, I. F. H., and J. J. Van der Watt. Carcinogenicity of sterigmatocystin to rat skin. Toxicol. Appl. Pharmacol. 26: 274–281, 1973.
 139. Pyerin, W. G., and E. Hecker. Epoxide activity in mouse skin epidermis. Z. Krebsforsch. 8: 81–83, 1975.
 140. Raick, A. N. Cell proliferation and promoting action in skin carcinogenesis. Cancer Res. 34: 920–926, 1974.
 141. Reimann, S. P., and E. M. Hall. Protective action of sulfhydryl against carcinogenesis induced with 1,2,5,6‐dibenzanthracene. Arch. Pathol. 22: 55–61, 1936.
 142. Ritchie, A. C., and U. Saffiotti. Orally administered 2‐acetyl‐aminofluorene as an initiator and as a promoter in epidermal carcinogenesis in the mouse. Cancer Res. 15 (2): 84–88, 1955.
 143. Robbins, J. H., K. H. Kraemer, M. A. Lutzner, B. W. Festoff, and H. G. Coon. Xeroderma Pigmentosum. An inherited disease with sun sensitivity, multiple cutaneous neoplasms and abnormal DNA repair. Ann. Internal Med. 80: 221–248, 1974.
 144. Roberts, J. J., and G. P. Warwick. The covalent binding of metabolites of dimethylaminoazobenzene, β‐naphthylamine and aniline to nucleic acids in vivo. Intern. J. Cancer 1: 179–196, 1966.
 145. Roe, F. J. C., and O. M. Glendenning. The carcinogenicity of β‐propiolactone for mouse skin. Brit. J. Cancer 10: 357–362, 1956.
 146. Roe, F. J. C., and M. H. Salaman. Further studies on incomplete carcinogenic triethylene melamine (T. E. M.). 1,2‐benzanthracene and β‐propiolactone, as initiators of skin tumour formation in the mouse. Brit. J. Cancer 9: 177–203, 1955.
 147. Rusch, H. P. Extrinsic factors that influence carcinogenesis. Physiol. Rev. 24: 177–204, 1944.
 148. Ryser, H. J. P. Chemical carcinogenesis. New Engl. J. Med. 285: 721–734, 1971.
 149. Saffiotti, U., and P. Shubik. Studies on promoting action in skin carcinogenesis. Natl. Cancer Inst. Monograph 10: 489–507, 1963.
 150. Salaman, M. H., and F. J. C. Roe. Incomplete carcinogens: ethyl carbamate (urethane) as an initiator of skin tumour formation in the mouse. Brit. J. Cancer 7: 472–481, 1953.
 151. Santamaria, L., G. G. Giordano, M. Alfisi, and F. Cascione. Effects of light on 3,4‐benzpyrene carcinogenesis. Nature 210: 824–825, 1966.
 152. Schlede, E., and A. H. Conney. Induction of benzo(a)pyrene hydroxylase activity in rat skin. Life Sci. 9: 1295–1303, 1970.
 153. Selkirk, J. K., R. G. Croy, and H. V. Gelboin. Benzo[a]pyrene metabolites: efficient and rapid separation by high‐pressure liquid chromatography. Science 184: 169–171, 1974.
 154. Selkirk, J. K., and C. Heidelberger. Isolation and partial purification of a mouse skin protein‐bound derivative of dibenz(a,h)anthracene (Abstract). Proc. Am. Assoc. Cancer Res. 13: 59, 1972.
 155. Selkirk, J. K., E. Huberman, and C. Heidelberger. An epoxide is an intermediate in the microsomal metabolism of the chemical carcinogen dibenz(a,h)anthracene. Biochem. Biophys. Res. Comm. 43: 1010–1016, 1971.
 156. Setlow, R. B., and J. D. Regan. Defective repair of Nacetoxy‐2‐acetylaminofluorene‐induced lesions in the DNA of xeroderma pigmentosum cells. Biochem. Biophys. Res. Commun. 46: 1019–1024, 1972.
 157. Shamberger, R. J., and G. Rudolph. Increase of lysosomal enzymes in skin cancers. Nature, London 213: 617–618, 1967.
 158. Shinozuka, H., and A. C. Ritchie. Pretreatment with croton oil, DNA synthesis, and carcinogenesis by carcinogen followed by croton oil. Intern. J. Cancer 2: 77–84, 1967.
 159. Shubik, P., A. R. Goldfarb, A. C. Ritchie, and H. Lisco. Latent carcinogenic action of beta‐irradiation on mouse epidermis. Nature, London 171: 934–936, 1953.
 160. Shubik, P., and J. L. Hartwell. Survey of compounds which have been tested for carcinogenic activity. Suppl. 1. Washington, D.C.: U. S. Govt. Printing Office, 1957.
 161. Shubik, P., and J. L. Hartwell. Survey of compounds which have been tested for carcinogenic activity. Suppl. 2. Washington, D.C.: U. S. Govt. Printing Office, 1969.
 162. Sims, P. Qualitative and quantitative studies on the metabolism of a series of aromatic hydrocarbons by rat‐liver preparations. Biochem. Pharmacol. 19: 795–818, 1970.
 163. Slaga, T. J., J. D. Scribner, and J. M. Rice. Physical binding of labeled 20‐methylcholanthrene to mouse epidermal subcellular fractions. Cancer Res. 33: 1032–1037, 1973.
 164. Smith, W. E., N. S. Cooper, and E. L. Wynder. Biological tests of fractions derived from cigarette smoke condensates. Proc. Am. Assoc. Cancer Res. 1: 45, 1954.
 165. Sommers, S. C., and R. G. McManus. Multiple arsenical cancers of skin and internal organs. Cancer 6: 347–359, 1953.
 166. Somogyi, A., S. Banerjee, M. M. Jacobson, J. Spranger, L. Achor, R. Kuntzman, and A. H. Conney. Studies on the metabolism and the carcinogenicity of benzo(a)pyrene in the skin of various strains of mice (Abstract). Proc. Am. Assoc. Cancer Res. 14: 442, 1973.
 167. Stenbäck, F., H. Garcia, and P. Shubik. Present status of the concept of promoting action and cocarcinogenesis in skin. Physiopathology 4: 1–63, 1973.
 168. Stevenson, I. H., and G. J. Dutton. Mechanism of glucuronide synthesis in skin (Abstract). Biochem. J. 77: 19, 1960.
 169. Stich, H. F., and B. A. Laishes. DNA repair and chemical carcinogens. Pathobiol. Ann. 341–376, 1973.
 170. Stich, H. F., and R. H. C. San. Reduced DNA repair synthesis in xeroderma pigmentosum cells exposed to the oncogenic 4‐nitroquinoline 1‐oxide and 4‐hydroxy‐aminoquinoline 1‐oxide. Mutat. Res. 13: 279–282, 1971.
 171. Stich, H. F., and R. H. C. San. DNA repair synthesis and cell survival of repair deficient human cells exposed to the K‐region epoxide of benz(a)anthracene. Proc. Soc. Exptl. Biol. Med. 142: 155, 1973.
 172. Stich, H. F., R. H. C. San, and Y. Kawazoe. Increased sensitivity of xeroderma pigmentosum cells to some chemical carcinogens and mutagens. Mutat. Res. 17: 127–137, 1973.
 173. Suntzeff, V., C. Carruthers, and E. V. Cowdry. The role of sebaceous glands and hair follicles in epidermal carcinogenesis. Cancer Res. 7: 439–443, 1947.
 174. Suntzeff, V., E. V. Cowdry, and A. Croninger. Microscopic visualization of the degeneration of sebaceous glands caused by carcinogens. Cancer Res. 15: 637–640, 1955.
 175. Takayama, S., N. Kuwabara, Y. Azama, and T. Sugimura. Skin tumors in mice painted with N‐methyl‐N′‐nitro‐N‐nitrosoguanidine and N‐ethyl‐N′‐Nitro‐N‐nitrosoguanidine. J. Natl. Cancer Inst. 46: 973–980, 1971.
 176. Tasseron, J. G., H. Diringer, N. Frohwirth, S. S. Mirvish, and C. Heidelberger. Partial purification of soluble protein from mouse skin to which carcinogenic hydrocarbons are specifically bound. Biochemistry 9: 1636–1644, 1970.
 177. Thomas, P. E., and J. J. Hutton. Genetics of aryl hydrocarbon hydroxylase induction in mice: additive inheritance in crosses between C3H/HeJ and DBA/2J. Biochem. Genetics 8: 249–257, 1973.
 178. Thomas, P. E., R. E. Kouri, and J. J. Hutton. The genetics of aryl hydrocarbon hydroxylase induction in mice: a single gene difference between C57BL/6J and DBA/2J. Biochem. Genetics 6: 157–168, 1972.
 179. Thomas, P. E., J. J. Hutton, and B. A. Taylor. Genetic relationship between aryl hydrocarbon hydroxylase inducibility and chemical carcinogen induced skin ulceration in mice. Genetics 74: 655–659, 1973.
 180. Ts'O, P. O. P., S. A. Lesko, and R. S. Umans. The physical binding and the chemical linkage of benzpyrene to nucleotides, nucleic acids and nucleohistones. In: Physico‐chemical mechanism of carcinogenesis, edited by E. D. Bergmann and B. Pullman. Jerusalem: Israel Acad. Sci. Humanities, 1969, p. 106–135.
 181. Ts'O, P. O. P., and P. Lu. Interaction of nucleic acids. I. Physical binding of thymine, adenine, steroids, and aromatic hydrocarbons to nucleic acids. Proc. Natl. Acad. Sci. 51: 17–24, 1964.
 182. Urbach, F. Modification of ultraviolet carcinogenesis by photoactive agents. J. Invest. Derm. 32: 373–378, 1959.
 183. Van Duuren, B. L. Carcinogenic epoxides, lactones, and haloethers and their mode of action. Ann. NY Acad. Sci. 163: 633–651, 1969.
 184. Van Duuren, B. L., and L. Orris. The tumor‐enhancing principles of Croton tiglium L. Cancer Res. 25: 1871–1875, 1965.
 185. Van Duuren, B. L., A. Sivak, C. Katz, and S. Melchionne. Tumorigenicity of acridine orange. Brit. J. Cancer 23: 587–590, 1969.
 186. Van Scott, E. J., S. Rothman, and C. R. Green. Studies on the sulfhydryl content of the skin. J. Invest. Derm. 20: 111–117, 1953.
 187. Vasiliev, J. M. The role of connective tissue proliferation in invasive growth of normal and malignant tissue; a review. Brit. J. Cancer. 12: 524–536, 1958.
 188. Vasiliev, J. M., and V. I. Guelstein. Local cell interactions in neoplasms and in foci of carcinogenesis. Progr. Exptl. Tumor Res. 8: 26–65, 1966.
 189. Viola, P. L., A. Bigotti, and A. Caputo. Oncogenic response of rat skin, lungs, and bones to vinyl chloride. Cancer Res. 31: 516–522, 1971.
 190. Wallcave, L., H. Garcia, R. Feldman, W. Lijinsky, and P. Shubik. Skin tumorigenesis in mice by petroleum asphalts and coal‐tar pitches of known polynuclear aromatic hydrocarbon content. Toxicol. Appl. Pharmacol. 18: 41–52, 1971.
 191. Wattenberg, L. W., and J. L. Leong. Histochemical studies of polycyclic hydrocarbon metabolizing systems (Abstract). J. Histochem. Cytochem. 10: 659, 1962.
 192. Wattenberg, L. W., and J. L. Leong. Inhibition of the carcinogenic action of benzo(a)pyrene by flavones. Cancer Res. 30: 1922–1925, 1970.
 193. Wattenberg, L. W., and J. L. Leong. Benzpyrene hydroxylase activity in mouse skin (Abstract). Proc. Am. Assoc. Cancer Res. 11: 81, 1970.
 194. Wattenberg, L. W., J. L. Leong, and P. J. Strand. Benzpyrene hydroxylase activity in the gastrointestinal tract. Cancer Res. 22: 1120–1125, 1962.
 195. Wattenberg, L. W., M. A. Page, and J. L. Leong. Induction of increased benzpyrene hydroxylase activity by flavones and related compounds. Cancer Res. 28: 934–937, 1968.
 196. Wheatley, D. N. Enhancement and inhibition of the induction by 7,12‐dimethylbenz(a)anthracene of mammary tumors in female Sprague‐Dawley Rats. Brit. J. Cancer 22: 787–792, 1968.
 197. Whitmire, C. E., R. A. Salerno, L. S. Rabstein, and R. J. Huebner. RNA tumor virus antigen expression in chemically induced tumors. Significance of specific chemical carcinogens to the derepression of the C‐type RNA virogene and oncogene expressions. In: Comparative Leukemia Research, 1971. (Bibliotheca Haematol. No. 39, 1972.)
 198. Wiebel, F. J., H. V. Gelboin, and H. G. Coon. Regulation of aryl hydrocarbon hydroxylase in intraspecific hybrids of human, mouse and hamster cells. Proc. Natl. Acad. Sci. 69: 3580–3584, 1972.
 199. Wiebel, F. J., H. V. Gelboin, N. P. Buu‐Hoi, M. G. Stout, and W. S. Burnham. Flavones and polycyclic hydrocarbons as modulators of aryl hydrocarbon (benzo[a]pyrene) hydroxylase. In: Model Studies in Chemical Carcinogenesis edited by P. O. P. Ts'O, and J. A. DiPaolo, New York: Marcel Dekker, 1974. p. 249–270.
 200. Wiebel, F. J., J. C. Leutz, L. Diamond, and H. V. Gelboin. Aryl hydrocarbon (benzo[a]pyrene) hydroxylase in microsomes from rat tissues: differential inhibition and stimulation by benzoflavones and organic solvents. Arch. Biochem. Biophys. 144: 78–86, 1971.
 201. Wiebel, F. J., J. C. Leutz, and H. V. Gelboin. Aryl hydrocarbon (benzo[a]pyrene) hydroxylase: inducible in extrahepatic tissues of mouse strains not inducible in liver. Arch. Biochem. Biophys. 154: 292–294, 1973.
 202. Wiebel, F. J., J. C. Leutz, and H. V. Gelboin. Aryl hydrocarbon (benzo[a]pyrene) hydroxylase: a mixed‐function oxygenase in mouse skin. J. Invest. Dermatol. 64: 184–189, 1975.
 203. Wynder, E. L., and D. Hoffman. The epidermis and the respiratory tract as bioassay systems in tobacco carcinogenesis. Brit. J. Cancer 24: 574–586, 1970.
 204. Yamagiwa, K., and K. Ichikawa. Experimental study of the pathogenesis of carcinoma. J. Cancer Res. 3: 1–29, 1918.
 205. Annual report of H. M. Chief Inspector of factories on industrial health, 1964. London: H. M. Stationery Office, 1969, p. 31.

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F. J. Wiebel, H. V. Gelboin. Cutaneous Carcinogenesis: Metabolic Interaction of Chemical Carcinogens with Skin. Compr Physiol 2011, Supplement 26: Handbook of Physiology, Reactions to Environmental Agents: 337-348. First published in print 1977. doi: 10.1002/cphy.cp090121