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4143301 
Journal Article 
AhR Mediated Hematotoxicity Is Induced At The Site Of Bone Marrow Where Consequent CYP2E1-Derived Benzene Metabolites Locally Induce Their Toxicity 
Hirabayashi, Y; Yoon, B; Li, G; Fujii-Kuriyama, Y; Kaneko, T; Kanno, J; Inoue, T 
2006 
1 
Toxicological Sciences
ISSN: 1096-6080
EISSN: 1096-0929 
TOX/6001114 
90 
1-S 
English 
We have reported that benzene-induced hemopoietic toxicity is transmitted by AhR. We also found that cytochrome P450 2E1 (CYP2E1) related to benzene metabolism is also up regulated in the bone marrow (BM) by benzene exposure in BM. Therefore, it is of interest to hypothesize a greater role of BM cells in hemopoietic toxicities rather than the hepatic metabolism. Accordingly, in the present study, benzene-induced hemopoietic toxicity was evaluated in wild type (Wt) mice after a lethal dose of whole-body irradiation followed by repopulation of BM cells that lack AhR or, vice versa, in AhR-KO (AhR-/-) mice after repopulation of Wt BM cells. As results, benzene-induced hemopoietic toxicity seems to have been transmitted through AhR, and benzene was transformed by de novo metabolism with CYP2E1 in the BM. The establishment of homozygous AhR-KO mice is described elsewhere. The BM repopulation assay was performed similarly to the assay of CFU-S, except that 106 BM cells were injected into lethally irradiated mice. One month after the transfusion of BM cells, the repopulated mice were used in the experiment. The benzene atmospheres were generated by heating liquid benzene to 16?C to form a vapor, and then the benzene-laden air was directed into 1.3 m3 inhalation chambers, followed by evaluation of hemopoietic parameters including number of hemopoietic progenitor cells. Mice that have been lethally irradiated and repopulated with BM cells from AhR-KO mice essentially did not show any benzene- induced hematotoxicity, implying that such toxicity is derived from de novo metabolisms with CYP2E1 in the BM other than hepatic metabolism. The present study raises two questions on AhR-mediated TCDD-induced hematotoxicity: Do Wt mice repopulated with AhR-KO BM cells show hematotoxicity by TCDD unlike in the case of benzene exposure? If such were the case, what would be the transmitter from the site of xenobiotic metabolic activation to the BM?