Dioxin-induced increase in leukotriene B4 biosynthesis through the aryl hydrocarbon receptor and its relevance to hepatotoxicity owing to neutrophil infiltration.

Dioxin and related chemicals alter the expression of a number of genes by activating the aryl hydrocarbon receptors (AHR) to produce a variety of disorders including hepatotoxicity. However, it remains largely unknown how these changes in gene expression are linked to toxicity. To address this issue, we initially examined the effect of 2,3,7,8-tetrachrolodibenzo--dioxin (TCDD), a most toxic dioxin, on the hepatic and serum metabolome in male pubertal rats and found that TCDD causes many changes in the level of fatty acids, bile acids, amino acids, and their metabolites.

Expression and physiological function of CYP4F subfamily in human eosinophils.

We investigated expression of the CYP4F subfamily in human leukocytes by flow cytometry using anti-CYP4F3A antibody and quantitative reverse transcription-polymerase chain reaction (QRT-PCR). More than 90% of CD11b, CD13, CD14, CD33, and eosinophil marker-positive cells expressed CYP4F3A. mRNA for CYP4F3A was found in neutrophils, monocytes, and eosinophils.

Inflammation resolved by retinoid X receptor-mediated inactivation of leukotriene signaling pathways.

Leukotrienes are implicated in the pathogenesis of diverse, inflammation-driven diseases. Metabolic inactivation of leukotriene signaling is an innate response to resolve inflammation, yet little is known of mechanisms regulating disposition of leukotrienes in peripheral tissues afflicted in common inflammatory diseases. We studied leukotriene hydroxylases (CYP4F gene products) in human skin, a common target of inflammation and adverse drug reactions.

Catalytic characterization and cytokine mediated regulation of cytochrome P450 4Fs in rat hepatocytes.

Cytochrome P450 (CYP) 4F mediated leukotriene B(4) (LTB(4)) metabolism modulates inflammation during injury and infection. Here we show that in addition to LTB(4), the recombinant rat CYP4Fs catalyze omega-hydroxylations of lipoxin A(4), and hydroxyeicosatetraeonic acids. CYP4F gene regulation studies in primary hepatocytes reveal that pro-inflammatory cytokines interleukin (IL) -1beta, IL-6 and tumor necrosis factor (TNF) -alpha produce a general inductive response whereas IL-10, an anti-inflammatory cytokine, suppresses CYP4F expression.

Expression and characterization of human cytochrome P450 4F11: Putative role in the metabolism of therapeutic drugs and eicosanoids.

We previously reported the cDNA cloning of a new CYP4F isoform, CYP4F11. In the present study, we have expressed CYP4F11 in Saccharomyces cerevisiae and examined its catalytic properties towards endogenous eicosanoids as well as some clinically relevant drugs. CYP4F3A, also known as a leukotriene B4 omega-hydroxylase, was expressed in parallel for comparative purposes.

Expression and induction of CYP4F subfamily in human leukocytes and HL60 cells.

We investigated the expression of the CYP4F subfamily in human leukocytes and HL60 cells. Enzymatic activity assay, immunocytochemical staining, and reverse transcription-polymerase chain reaction (RT-PCR) analysis of human leukocytes showed that polymorphonuclear leukocytes (PMNs) expressed CYP4F3B and CYP4F12 in addition to CYP4F3. Transcription start site of CYP4F3B mRNA in the leukocytes was identical to that of CYP4F3 mRNA.

Prostaglandin and leukotriene omega-hydroxylases.

Omega and subterminal hydroxylations of prostaglandins (PGs), leukotriene B4 (LTB4) and some related eicosanoids are catalyzed by the cytochrome P450 (CYP) enzymes belonging to the CYP4A and CYP4F subfamilies. CYP4A4, which is induced in pregnant rabbits, is the only elucidated PGE omega-hydroxylase within the CYP4A subfamily. CYP4F3 is the most tissue specific and most efficient LTB4 omega-hydroxylase, judging from its restricted localization in human polymorphonuclear leukocytes (PMN) and its very low Km value for LTB4.