title: Aryl hydrocarbon receptor mediates benzene-induced hematotoxicity.
abstract: Benzene can induce hematotoxicity and leukemia in humans and mice. Since a review of the literature shows that the CYP2E1 knockout mouse is not known to possess any benzene toxicity, the metabolism of benzene by CYP2E1 in the liver is regarded to be prerequisite for its cytotoxicity and genotoxicity, although the mechanism is not fully understood yet. Because it was found some years ago that benzene was also a substrate for CYP1A1, we investigated the involvement of the aryl hydrocarbon receptor (AhR) in benzene hematotoxicity using AhR wild-type (AhR(+/+)), heterozygous (AhR(+/-)), and homozygous (AhR(-/-)) male mice. Interestingly, following a 2-week inhalation of 300 ppm benzene (a potent dose for leukemogenicity), no hematotoxicity was induced in AhR(-/-) mice. Further, there were no changes in cellularity of peripheral blood and bone marrow (BM), nor in levels of granulocyte-macrophage colony-forming units in BM. This lack of hematotoxicity was associated with the lack of p21 overexpression, which was regularly seen in the wild-type mice following benzene inhalation. Combined treatment with two major benzene metabolites, phenol and hydroquinone, induced hemopoietic toxicity, although it was not known whether this happened due to a surprising lack of expression of CYP2E1 by AhR knockout, or due to a lack of other AhR-mediated CYP enzymes, including 1A1 (i.e., a possible alternative pathway of benzene metabolism). The former possibility, evaluated in the present study, failed to show a significant relationship between AhR and the expression of CYP2E1. Furthermore, a subsequent evaluation of AhR expression after benzene inhalation tended to show higher but less significant expression in the liver, and none in the BM, compared with sham control. Although this study failed to identify the more likely of the above-mentioned two possibilities, the study using AhR knockout mice on benzene inhalation presents the unique possibility that the benzene toxicity may be regulated by AhR signaling.
authors.affiliation: Division of Cellular and Molecular Toxicology, National Institute of Health Sciences, 1-18-1 Kamiyohga, Setagayaku, Tokyo 158-8501, Japan.
authors.forename: Byung-Il
authors.initials: BI
authors.lastname: Yoon
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kawasaki
authors.forename: Yukio
authors.initials: Y
authors.lastname: Kodama
authors.forename: Toyozo
authors.initials: T
authors.lastname: Kaneko
authors.forename: Jun
authors.initials: J
authors.lastname: Kanno
authors.forename: Dae-Yong
authors.initials: DY
authors.lastname: Kim
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Fujii-Kuriyama
authors.forename: Tohru
authors.initials: T
authors.lastname: Inoue
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001554:Benzene / Q000633:toxicity*; D001772:Blood Cell Count; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis; D019392:Cytochrome P-450 CYP2E1 / Q000096:biosynthesis; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D006873:Hydroquinones / Q000633:toxicity; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019800:Phenol / Q000633:toxicity; D012333:RNA, Messenger / Q000032:analysis; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics / Q000378:metabolism*
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D006873:Hydroquinones; D012333:RNA, Messenger; D018336:Receptors, Aryl Hydrocarbon; D019800:Phenol; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019392:Cytochrome P-450 CYP2E1; D001554:Benzene; C031927:hydroquinone