CYP4F3B is induced by PGA1 in human liver cells: a regulation of the 20-HETE synthesis

Abstract

The regulation of the human liver-specific cytochrome P450 4F3B (CYP4F3B) isoform, a splice variant of the CYP4F3 gene with strong substrate specificity for long chain fatty acids, is yet an unsolved question. This report provides the first evidence that CYP4F3B is uniquely induced by prostaglandin A 1 (PGA 1 ) in human hepatocyte-like

Role of Cytochrome P450s in Inflammation

“…CYP4F8 is associated with prostate cancer based on expression studies (Vainio et al, 2011). with hypertension and changes in urinary 20-HETE levels in a number of patient populations (Wu et al, 2014). Induction of CYP4F3B expression results in higher levels of 20-HETE synthesis in cultured human liver cells (Antoun et al, 2008;Plee-Gautier et al, 2012). The ω-3 PUFAs EPA and DHA are also substrates for ω-hydroxylation by CYP4F3B in vitro, and they competitively inhibit conversion of arachidonic acid to 20-HETE (Harmon et al, 2006).…”

CYP4F3B Expression Is Associated with Differentiation of HepaRG Human Hepatocytes and Unaffected by Fatty Acid Overload

“…This confirmed that HepaRG cells preserved the ability to metabolize C18 epoxides with high efficiency via the same pathways as in the liver (Capdevila et al, 1988). Note that CYP4F3B was also identified as the enzyme producing 20-HETE in HepaRG cells (Antoun et al, 2008). This functional feature of HepaRG cells offers new clues to highlight the mechanisms of toxicity induced by FA derivatives described as toxic metabolites in mammals but also by epoxyeicosatrienoic acids, found to accumulate in alcoholic liver disease in rat (French et al, 1997).…”

“…Proteins (50 g) from HepaRG cells were resolved on 4 to 12% gradient SDS-polyacrylamide gel electrophoresis, transferred onto nitrocellulose, and blotted with either CYP4F3B-specific anti-peptide antibody raised against the amino acids encoded by the CYP4F3B-specific exon (position 232-374 from sequence AF05482 as described previously) (Antoun et al, 2008) (Eurogentec, Seraing, Belgium) or rabbit anti-CYP4A11 primary polyclonal antibody (ref: RDI, -CYP4A11abr; RDI). After washing with PBS, they were treated with PBS containing an anti-rabbit Ig-biotinylated species-specific secondary antibody conjugated to streptavidin-horseradish peroxidase and washed with PBS.…”

“…In addition, expression of CYP4A/4F gene families can be highly modulated by various environmental factors, for instance, fasting, high-fat diet, hypolipidemic drugs, or peroxisome proliferators (Hardwick, 2008;Hardwick et al, 2009), and by an endogenous lipid mediator such as prostaglandin A1 (Antoun et al, 2008). Moreover, different intracellular types of FAs and their metabolites may coordinate energy homeostasis by activation or repression of distinct transcriptional factors including peroxisome proliferators-activated receptors (PPAR␣, PPAR␤, PPAR␥), sterol regulatory element-binding proteins (SREBP-1 and SREBP-2), and liver X receptor (LXR␣), suggesting involvement of distinct signaling pathways.…”

CYP4 Enzymes As Potential Drug Targets: Focus on Enzyme Multiplicity, Inducers and Inhibitors, and Therapeutic Modulation of 20- Hydroxyeicosatetraenoic Acid (20-HETE) Synthase and Fatty Acid ω- Hydroxylase Activities

“…CYP4F3B mRNA is induced in HepaRG cells by prostaglandin A1 in a concentration-dependent manner (1.8-6-fold after 1–40 μM PGA1 treatment) [30]. In contrast, basal CYP4F3A mRNA was low in the cells and was not inducible by PGA1.…”