Elevated expression of CYP4F3 associated with occupational benzene‐induced hepatotoxicity and induction of CYP4F3 by benzene metabolites in HL60 cells

Abstract

Benzene is an established human carcinogen and leukemogen. Although the mechanism remains uncertain, an initial metabolism and bioactivation of benzene, especially by cytochrome P450 2E1 in the liver, was considered to be a prerequisite. To further identify the other members of the CYP family associated with benzene‐induced hematotoxicity, a cDNA microarray containing 32 cytochrome P450 genes was used. Seven female shoe‐manufacture workers with different hematological disorders were recruited, and seven age‐ and gender‐matched normal subjects were selected as controls. Total RNA from the two groups was purified, and reverse transcription to cDNAs with concomitant incorporation of fluorescent dCTP. The cDNAs was then hybridized to the microarray chips. Genes with a two‐fold higher/lower expression level were considered to be significant. Our results revealed that six CYP genes (CYP4F3, CYP1A1, CYP27A1, CYP1B1, CYP2B6, and CYP51) were found to be differentially expressed between benzene‐exposed patients and controls. Among these, CYP4F3 gene, which encodes the leukotriene B4 ω‐hydroxylase, was up‐regulated consistently among all patients. To further analyze the mechanism of elevation of CYP4F3, HL60 cells were treated with benzene and metabolites. Benzene metabolite phenol induces CYP4F3 similarly to all‐trans‐retinoic acid albeit at a higher concentration, whereas hydroquinone strongly induces apoptosis. Our study indicated that CYP4F3 is up‐regulated in human peripheral blood cells that is correlated with benzene toxicity and thus, may serve as a new biomarker for exposure and poisoning of benzene.