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. The molecular mechanism behind IL-6 related induction of CYP4F4 and 4F5 is partially signal transducer and activator of transcription 3 (STAT3) dependent. When hepatocytes are subjected to high concentrations of LTB(4) or prostaglandin E(2), lipid mediators of inflammation, only an increase in CYP4F5 mRNA expression is observed. Collectively, the results from isozyme activity and substrate driven CYP4F induction do not support the notion that an autoregulatory pathway could control the excessive concentrations of LTB(4) during an inflammatory challenge to hepatocytes.