Role of mammary epithelial and stromal P450 enzymes in the clearance and metabolic activation of 7,12-dimethylbenz(a)anthracene in mice

Abstract

Microsomal cytochrome P450 (P450) enzymes, which are important in the metabolism of carcinogens, are expressed in both epithelial and stromal cells in the mammary gland. The aim of this study was to investigate the roles of mammary epithelial P450 enzymes in the bioactivation and disposition of 7,12-dimethylbenz(a)anthracene (DMBA), a breast carcinogen, in the mammary gland. A new mouse model (named MEpi-Cpr-null) was produced, wherein P450 activities in the mammary epithelial cells are suppressed through tissue-specific deletion of the gene for P450 reductase (Cpr), an enzyme required for the activities of all microsomal P450 enzymes. Comparisons between wild-type and MEpi-Cpr-null mice showed that the tissue-specific deletion of Cpr in the mammary epithelial cells was accompanied by significant increases in the levels of DMBA and DMBA–DNA adduct in the mammary gland following a single intraperitoneal injection of DMBA at 50mg/kg. Immunohistochemical and immunoblot analysis further revealed greater induction of CYP1B1 expression by the DMBA treatment in the mammary stroma of the MEpi-Cpr-null mice than in that of the WT mice. These findings not only demonstrate that the epithelial P450 enzymes play important roles in the clearance of DMBA, but also suggest that P450 enzymes in both mammary epithelial and stromal cells contribute to carcinogen-mediated DNA damage.