Abstract
Exposure to benzene elicits a spectrum of hematotoxicity ranging from reduction of peripheral blood cell counts to aplastic anemia and leukemia. The molecular mechanism by which benzene damages hematopoietic cells is unclear; in particular, benzene-induced aberrant gene expression has not been addressed. We analyzed differential gene expression in the peripheral white blood cells from seven female patients with occupational benzene poisoning and seven matched control subjects. In this study, we report altered expression of cytochrome P450 in the patients. All patients exhibited elevated expression of CYP4F3A encoding the leukotriene B4 (LTB4) ω-hydroxylase critical in the inactivation of LTB4 in polymorphonuclear leukocytes with a -fold induction between 3 and 71. Four patients had high expression of CYP1A1, and two patients had elevated expression of CYP1B1. Expressions of CYP2B6, CYP51, and CYP27A1 were also altered in certain patients. Mechanistic analysis revealed that phenol, a major metabolite of benzene, significantly induced the expression of CYP4F3A at both mRNA and protein levels in cultured promyelocytic leukemia cells (HL-60), similarly to all-trans retinoic acid. Induction of CYP4F3 by phenol was also observed in differentiated HL-60 cells, in the proerythroid cell line K562, and ex vivo in human neutrophils. On the other hand, hydroquinone induced extensive apoptosis of the cells. The findings demonstrated, for the first time, that benzene and metabolites induce CYP4F3 in human blood cells both in vivo and in vitro. Induction of CYP4F3 may play a role in the development of benzene hematotoxicity and serve as a biomarker of benzene exposure.
Footnotes
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This work was supported in part by the National Nature Science Foundation, China [Grants 30571556, 30771784]; the Hubei Provincial Nature Science Foundation, Hubei, China [Grant 2001ABB161]; and the National Institute for Occupational Safety and Health [Grant 8927007B].
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Z.Z. and X.H. contributed equally to this work.
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.023192.
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ABBREVIATIONS: P450, cytochrome P450; WBC, white blood cell; LTB4, leukotriene B4; PMN, polymorphonuclear leukocyte; IMDM, Iscove's modified Dulbecco's medium; FBS, fetal bovine serum; ATRA, all-trans retinoic acid; DMSO, dimethyl sulfoxide; CT, threshold cycle; PCR, polymerase chain reaction; FACS, fluorescence-activated cell sorting; NBT, nitroblue tetrazolium; PMA, phorbol myristate acetate; AML, acute myelogenous leukemia.
- Received July 1, 2008.
- Accepted November 20, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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