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Induction of CYP4F3 by Benzene Metabolites in Human White Blood Cells in Vivo in Human Promyelocytic Leukemic Cell Lines and ex Vivo in Human Blood Neutrophils

Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, China (Z.Z., Y.B., Y.X., N.T., L.L.); and Receptor Biology Laboratory, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Centers for Disease Control and Prevention, Morgantown, West Virginia (Z.Z., X.H., Q.M.)

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) -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.