Cytochrome P4501B1 mediates induction of bone marrow cytotoxicity and preleukemia cells in mice treated with 7,12-dimethylbenz[a]anthracene

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 bioactiva tion by P-450 cytochromes to dihydrodiol epoxides. The recently identified cytochrome P4501B1 (CYP1B1) bioactivates PAHs but is also a physiological r egulator, 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 e ffects of the prototypic PAH 7,12-dimethylbenz[a]anthracene (DMBA), CYP1B1 null mice did not produce the appreciable amounts of bone marrow DMBA dihyd rodiol epoxide DNA adducts present in wild-type mice, despite comparable he patic inductions of the prominent PAM-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 DMB A dihydrodiol epoxides in the bone marron. Furthermore, this study substant iates the importance of DMBA dihydrodiol epoxide generation at the site of cancer initiation and suggests that tissue-specific constitutive CYP1B1 exp ression may contribute to cancer susceptibility in the human population.