RT Journal Article
SR Electronic
T1 Bone Marrow Stromal Cell Cytochrome P4501B1 Is Required for Pre-B Cell Apoptosis Induced by 7,12-Dimethylbenz[a]anthracene
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1317
OP 1323
DO 10.1124/mol.56.6.1317
VO 56
IS 6
A1 Shawn M. Heidel
A1 Karrie Holston
A1 Jeroen T.M. Buters
A1 Frank J. Gonzalez
A1 Colin R. Jefcoate
A1 Charles J. Czupyrynski
YR 1999
UL http://molpharm.aspetjournals.org/content/56/6/1317.abstract
AB We previously demonstrated that murine bone marrow stromal cells express high levels of cytochrome P4501B1 (CYP1B1) that metabolizes 7,12-dimethylbenza[a]anthracene (DMBA), and that DMBA activates the Ah receptor (AhR) in these cells in vitro. More recently, we reported that CYP1B1 is required for DMBA-induced lymphoblastoma formation in vivo. In this study, we addressed the hypothesis that bone marrow stromal cell CYP1B1, and not AhR activation, is required for DMBA-induced pre-B-cell apoptosis. Although DMBA did not directly cause apoptosis in pre-B cells, dose-dependent apoptosis of pre-B cells was observed when they were cocultured with a bone marrow stromal cell line. The DMBA 3,4-dihydrodiol metabolite was more potent in effecting pre-B-cell apoptosis than DMBA, whereas the potent AhR agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin was inactive. Both pre-B cells and bone marrow stromal cells contained DMBA-diol-epoxide DNA adducts, indicating that reactive metabolites were transferred from stromal cells to pre-B cells. DMBA caused apoptosis when cocultured with primary bone marrow stromal cells isolated from AhR-null mice but not CYP1B1-null mice. When cocultured with AhR-null primary bone marrow stromal cells, DMBA induced approximately 50% of the pre-B-cell apoptosis seen with stromal cells from AhR-heterozygous mice. This reduced level of apoptosis parallels the decreased CYP1B1 expression in AhR-null mouse bone marrow stromal cells. These findings provide convincing evidence that bone marrow stromal cell CYP1B1 metabolism of DMBA, but not AhR activation, is required for DMBA-induced pre-B-cell apoptosis.