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[Cancer Research 60, 3454-3460, July 1, 2000]
© 2000 American Association for Cancer Research

Carcinogenesis

Cytochrome P4501B1 Mediates Induction of Bone Marrow Cytotoxicity and Preleukemia Cells in Mice Treated with 7,12-Dimethylbenz[a]anthracene1

Shawn M. Heidel, Peter S. MacWilliams, William M. Baird, W. Mohaiza Dashwood, Jeroen T. M. Buters, Frank J. Gonzalez, Michele C. Larsen, Charles J. Czuprynski2 and Colin R. Jefcoate2, 3

Department of Pathobiological Sciences [S. M. H., P. S. M., C. J. C.], Environmental Health Sciences Center [S. M. H., M. C. L., C. J. C., C. R. J.], and Department of Pharmacology [M. C. L., C. R. J.], University of Wisconsin, Madison, Wisconsin 53706; Environmental Health Sciences Center, Oregon State University, Corvalis, Oregon 97331 [W. M. B., W. M. D.]; Institute of Toxicology and Environmental Health, Technical University of Munich, Munich D-80636, Germany [J. T. M. B.]; and National Cancer Institute, Bethesda, Maryland 20892 [F. J. G.]

Humans are exposed to polycyclic aromatic hydrocarbons (PAHs) through many environmental pollutants, especially cigarette smoke. These chemicals cause a variety of tumors and immunotoxic effects, as a consequence of bioactivation by P-450 cytochromes to dihydrodiol epoxides. The recently identified cytochrome P4501B1 (CYP1B1) bioactivates PAHs but is also a physiological regulator, as evidenced by linkage of CYP1B1 deficiency to congenital human glaucoma. This investigation demonstrates that CYP1B1 null mice are almost completely protected from the acute bone marrow cytotoxic and preleukemic effects of the prototypic PAH 7,12-dimethylbenz[a]anthracene (DMBA). CYP1B1 null mice did not produce the appreciable amounts of bone marrow DMBA dihydrodiol epoxide DNA adducts present in wild-type mice, despite comparable hepatic inductions of the prominent PAH-metabolizing P-450 cytochrome, CYP1A1. Wild-type mice constitutively expressed low levels of bone marrow CYP1B1. These findings suggest that CYP1B1 is responsible for the formation of DMBA dihydrodiol epoxides in the bone marrow. Furthermore, this study substantiates the importance of DMBA dihydrodiol epoxide generation at the site of cancer initiation and suggests that tissue-specific constitutive CYP1B1 expression may contribute to cancer susceptibility in the human population.




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