Bone marrow cytotoxicity of benzo[a]pyrene is dependent on CYP1B1 but is diminished by Ah receptor-mediated induction of CYP1A1 in liver

Abstract

We have previously used CYP1B1-null mice to demonstrate that dimethylbenz(a)anthracene (DMBA) requires CYP1B1 for bone marrow (BM) toxicity. Benzo(a)pyrene (BP), a much more potent Ah receptor ligand, shows very different responses that nevertheless depend on CYP1B1. Wild-type (AhR(b)) mice treated with DMBA for 48 h exhibit a large loss in BM cellularity and disruption of marrow structure that is not seen for BP treatment. In congenic mice with a low affinity AhR (AhR(d)), DMBA and BP are equally toxic to the BM whereas AhR(d) x CYP1B1-null mice are fully protected. In situ hybridization demonstrates that CYP1B1 mRNA is constitutively expressed in marrow cells and is induced by PAHs according to their AhR affinity (BP>DMBA), including lower levels in AhR(d) mice. Importantly, expression of CYP1A1 mRNA was undetectable in BM. In wild-type mice, BP treatment leads to a fivefold greater induction of hepatic CYP1A1 than that of DMBA treatment. Neither induction occurs in AhR(d) mice. Thus, hepatic metabolism may prevent BP from reaching the BM, where it can be bioactivated by CYP1B1. Flow cytometric analyses of BM cells showed that there were decreases in granulocytes and lymphocytes following DMBA treatment, but not after BP treatment. These data suggest that there is an inverse relationship between liver metabolism and BM toxicity resulting from limitations on the delivery of PAH to CYP1B1 present in BM, where only very low constitutive levels are needed.