This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kapitulnik, J. Articles by Conney, A. H. Search for Related Content PubMed PubMed Citation Articles by Kapitulnik, J. Articles by Conney, A. H.

Tumorigenicity Studies with Diol-Epoxides of Benzo(a)pyrene Which Indicate That (±)-trans-7ß,8-Dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene Is an Ultimate Carcinogen in Newborn Mice

Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., Nutley, New Jersey 07110 [J. K., P. G. W., W. L., A. H. C.], and Section on Oxidation Mechanisms, Laboratory of Chemistry, National Institute of Arthritis, Metabolism and Digestive Diseases, NIH, Bethesda, Maryland 20014 [H. Y., D. M. J.]

The tumorigenic activities of benzo(a)pyrene (BP), (±)-trans-7ß,8-dihydroxy-9ß,10ß-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 1), (±)-trans-7ß,8-dihydroxy-9,10-epoxy-7,8,9,10-tetrahydrobenzo(a)pyrene (diol-epoxide 2), (±)-trans-7,8,-dihydroxy-7,8-dihydrobenzo(a)pyrene (BP 7,8-dihydrodiol), and the tetraols derived from the hydrolysis of diol-epoxide 2 were evaluated in newborn mice. The mice were given injections sequentially of 4, 8, and 16 nmoles of each compound on the first, eighth, and fifteenth days of life, and the animals were killed when they were 28 weeks old. Diol-epoxide 1 was highly toxic in newborn mice, and most of the animals treated with this compound died before weaning. Diol-epoxide 2 and BP 7,8-dihydrodiol were, respectively, about 40- and 15-fold more active than BP in causing pulmonary adenomas. Vehicle-treated control animals had an average of 0.13 lung adenoma/mouse, whereas animals treated with BP, BP 7,8-dihydrodiol, or diol-epoxide 2 had, respectively, 0.24, 1.77, and 4.42 pulmonary adenomas/mouse. Diol-epoxide 1 and the tetraols derived from diol-epoxide 2 did not induce pulmonary adenomas. The inactivity of diol-epoxide 1 under the conditions of our study should be interpreted with caution because of the high toxicity of this compound. The results of our study provide evidence that BP 7,8-dihydrodiol is a proximate carcinogenic metabolite and that diol-epoxide 2 is an ultimate carcinogenic metabolite of BP in the newborn mouse.

¹ Present address: Department of Pharmacology, Hadassah-Hebrew University Medical School, Jerusalem, Israel.

² Present address: Eppley Institute for Research in Cancer, University of Nebraska Medical Center, 42nd and Dewey Avenue, Omaha, Nebr. 68105.

³ To whom requests for reprints should be addressed, at Department of Biochemistry and Drug Metabolism, Hoffmann-La Roche Inc., Nutley, N. J. 07110.

Received 8/ 5/77. Accepted 11/10/77.

This article has been cited by other articles:

				V. K. Batra, D. D. Shock, R. Prasad, W. A. Beard, E. W. Hou, L. C. Pedersen, J. M. Sayer, H. Yagi, S. Kumar, D. M. Jerina, et al. Structure of DNA polymerase beta with a benzo[c]phenanthrene diol epoxide-adducted template exhibits mutagenic features PNAS, November 14, 2006; 103(46): 17231 - 17236. [Abstract] [Full Text] [PDF]

				K. Iskander, A. Gaikwad, M. Paquet, D. J. Long II, C. Brayton, R. Barrios, and A. K. Jaiswal Lower Induction of p53 and Decreased Apoptosis in NQO1-Null Mice Lead to Increased Sensitivity to Chemical-Induced Skin Carcinogenesis Cancer Res., March 15, 2005; 65(6): 2054 - 2058. [Abstract] [Full Text] [PDF]

				D. Schwarz, P. Kisselev, and I. Roots St. John's Wort Extracts and Some of Their Constituents Potently Inhibit Ultimate Carcinogen Formation from Benzo[a]pyrene-7,8-Dihydrodiol by Human CYP1A1 Cancer Res., November 15, 2003; 63(22): 8062 - 8068. [Abstract] [Full Text] [PDF]

				S. Chen, N. Nguyen, K. Tamura, M. Karin, and R. H. Tukey The Role of the Ah Receptor and p38 in Benzo[a]pyrene-7,8-dihydrodiol and Benzo[a]pyrene-7,8-dihydrodiol-9,10-epoxide-induced Apoptosis J. Biol. Chem., May 23, 2003; 278(21): 19526 - 19533. [Abstract] [Full Text] [PDF]

				T. Shimada, K. Inoue, Y. Suzuki, T. Kawai, E. Azuma, T. Nakajima, M. Shindo, K. Kurose, A. Sugie, Y. Yamagishi, et al. Arylhydrocarbon receptor-dependent induction of liver and lung cytochromes P450 1A1, 1A2, and 1B1 by polycyclic aromatic hydrocarbons and polychlorinated biphenyls in genetically engineered C57BL/6J mice Carcinogenesis, July 1, 2002; 23(7): 1199 - 1207. [Abstract] [Full Text] [PDF]

				D. C. Spink, B. H. Katz, M. M. Hussain, B. C. Spink, S. J. Wu, N. Liu, R. Pause, and L. S. Kaminsky Induction of CYP1A1 and CYP1B1 in T-47D Human Breast Cancer Cells by Benzo[a]pyrene Is Diminished by Arsenite Drug Metab. Dispos., March 1, 2002; 30(3): 262 - 269. [Abstract] [Full Text] [PDF]

				H. Rubin Synergistic mechanisms in carcinogenesis by polycyclic aromatic hydrocarbons and by tobacco smoke: a bio-historical perspective with updates Carcinogenesis, December 1, 2001; 22(12): 1903 - 1930. [Abstract] [Full Text] [PDF]

				T. Shimada, Y. Oda, E. M. J. Gillam, F. P. Guengerich, and K. Inoue Metabolic Activation of Polycyclic Aromatic Hydrocarbons and Other Procarcinogens by Cytochromes P450 1A1 and P450 1B1 Allelic Variants and Other Human Cytochromes P450 in Salmonella typhimurium NM2009 Drug Metab. Dispos., September 1, 2001; 29(9): 1176 - 1182. [Abstract] [Full Text] [PDF]

				D. J. Long II, R. L. Waikel, X.-J. Wang, D. R. Roop, and A. K. Jaiswal NAD(P)H : quinone Oxidoreductase 1 Deficiency and Increased Susceptibility to 7,12-Dimethylbenz[a]-anthracene-Induced Carcinogenesis in Mouse Skin J Natl Cancer Inst, August 1, 2001; 93(15): 1166 - 1170. [Abstract] [Full Text] [PDF]

				J.A. Williams Single nucleotide polymorphisms, metabolic activation and environmental carcinogenesis: why molecular epidemiologists should think about enzyme expression Carcinogenesis, February 1, 2001; 22(2): 209 - 214. [Abstract] [Full Text] [PDF]

				J. A. Williams and D. H. Phillips Mammary Expression of Xenobiotic Metabolizing Enzymes and Their Potential Role in Breast Cancer Cancer Res., September 1, 2000; 60(17): 4667 - 4677. [Abstract] [Full Text]

				F. P. Guengerich Metabolism of chemical carcinogens Carcinogenesis, March 1, 2000; 21(3): 345 - 351. [Abstract] [Full Text] [PDF]

				T. E. Gram Chemically Reactive Intermediates and Pulmonary Xenobiotic Toxicity Pharmacol. Rev., December 1, 1997; 49(4): 297 - 342. [Abstract] [Full Text] [PDF]

				J. P. GLUSKER, D. E. ZACHARIAS, D. L. WHALEN, S. FRIEDMAN, and T. M. POHL Internal Hydrogen Bond Formation in a syn-Hydroxyepoxide Science, February 5, 1982; 215(4533): 695 - 696. [Abstract] [PDF]