Identification of CYP4F8 in Human Seminal Vesicles as a Prominent 19-Hydroxylase of Prostaglandin Endoperoxides

Bylund, Johan; Hidestrand, Mats; Ingelman‐Sundberg, Magnus; Oliw, Ernst H.

doi:10.1074/jbc.m001712200

Cited by 76 publications

(55 citation statements)

References 35 publications

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“…These results indicate that CYP4A1 accounts for the majority of microsomal 14,15-and 8,9-EET hydroxylation and that other cytochrome P450 isoforms are probably responsible for most of the microsomal 11,12-EET hydroxylation. The /-1-hydroxylation of arachidonic acid and of several eicosanoids by CYP1A, CYP2C, CYP2J, and CYP4F isoforms has been documented (37)(38)(39)(40)(41).…”

Section: Figmentioning

confidence: 99%

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

Cowart

Wei²,

Hsu

et al. 2002

Journal of Biological Chemistry

178

152

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Cytochromes P450 of the CYP2C and CYP4A gene subfamilies metabolize arachidonic acid to 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) and to 19-and 20-hydroxyeicosatetraenoic acids (HETEs), respectively. Abundant functional studies indicate that EETs and HETEs display powerful and often opposing biological activities as mediators of ion channel activity and regulators of vascular tone and systemic blood pressures. Incubation of 8,9-, 11,12-, and 14,15-EETs with microsomal and purified forms of rat CYP4A isoforms led to rapid NADPH-dependent metabolism to the corresponding 19-and 20-hydroxylated EETs. Comparisons of reaction rates and catalytic efficiency with those of arachidonic and lauric acids showed that EETs are one of the best endogenous substrates so far described for rat CYP4A isoforms. CYP4A1 exhibited a preference for 8,9-EET, whereas CYP4A2, CYP4A3, and CYP4A8 preferred 11,12-EET. In general, the closer the oxido ring is to the carboxylic acid functionality, the higher the rate of EET metabolism and the lower the regiospecificity for the EET -carbon. Analysis of cis-parinaric acid displacement from the ligand-binding domain of the human peroxisome proliferator-activated receptor-␣ showed that -hydroxylated 14,15-EET bound to this receptor with high affinity (K i ‫؍‬ 3 ؎ 1 nM). Moreover, at 1 M, the -alcohol of 14,15-EET or a 1:4 mixture of the -alcohols of 8,9-and 11,12-EETs activated human and mouse peroxisome proliferator-activated receptor-␣ in transient transfection assays, suggesting a role for them as endogenous ligands for these orphan nuclear receptors.Cytochromes P450 of the CYP4A gene subfamily are structurally and functionally conserved fatty-acid hydroxylases that are expressed in most mammalian tissues, including rat and human kidney and liver (1-7). These enzymes are selective for the /-1-hydroxylation of saturated and unsaturated fatty acids (1-7) and lack known roles in drug metabolism. The expression of some CYP4A isoforms is under the control of the peroxisome proliferator-activated receptor-␣ (PPAR␣) 1 (8 -13) and regulated by a variety of physiological and pathophysiological stimuli, including dietary fatty acids, hormones, diabetes, and starvation (9 -13). Interest in the molecular and functional properties of these enzymes has been stimulated by the demonstration of their role in the /-1-hydroxylation of arachidonic acid (AA) (4 -7) and the powerful biological activities of 19-and 20-hydroxyeicosatetraenoic acids (HETEs) as modulators of renal ion fluxes and vasoactivity (14 -18). Based on biochemical and functional correlates of CYP4A renal expression, 20-HETE biosynthesis, and the onset of systemic high blood pressure in the SHR/WKY rat model of spontaneous hypertension, a pro-hypertensive role for 20-HETE and CYP4A isoforms was proposed (14).The cytochrome P450 AA epoxygenase catalyzes the in vivo regio-and enantioselective metabolism of AA to epoxyeicosatrienoic acids (EETs) (16). Studies with microsomal and/or purified cytochrome P450 preparations showed tha...

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Section: Figmentioning

confidence: 99%

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

Cowart

Wei²,

Hsu

et al. 2002

Journal of Biological Chemistry

178

152

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“…Recombinant P450 protein and intestinal microsomes were incubated with ebastine of optional concentrations for 30 minutes at 37°C in the presence of an NADPH-generating system. (Bylund et al, 2000(Bylund et al, , 2001, unlike the other P450 4F enzymes (Jin et al, 1998;Kikuta et al, 1998;Christmas et al, 2001). A glycine residue (Gly-328) in SRS-4 of P450 4F8 and 4F12 would be likely to contribute to the position specificity for v2-and v3-hydroxylation of arachidonic acid (Stark et al, 2005).…”

Section: Tablementioning

confidence: 99%

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

Uehara

Uno

Yuki

et al. 2016

Drug Metabolism and Disposition

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Common marmosets (Callithrix jacchus) are attracting attention as animal models in preclinical studies for drug development. However, cytochrome P450s (P450s), major drug-metabolizing enzymes, have not been fully identified and characterized in marmosets. In this study, based on the four novel P450 4F genes found on the marmoset genome, we successfully isolated P450 4F2, 4F3B, 4F11, and 4F12 cDNAs in marmoset livers. Deduced amino acid sequences of the four marmoset P450 4F forms exhibited high sequence identities (87%-93%) to the human and cynomolgus monkey P450 4F homologs. Marmoset P450 4F3B and 4F11 mRNAs were predominantly expressed in livers, whereas marmoset P450 4F2 and 4F12 mRNAs were highly expressed in small intestines and livers. Four marmoset P450 4F proteins heterologously expressed in Escherichia coli catalyzed the v-hydroxylation of leukotriene B 4 . In addition, marmoset P450 4F12 effectively catalyzed the hydroxylation of antiallergy drug ebastine, a human P450 2J/4F probe substrate. Ebastine hydroxylation activities by small intestine and liver microsomes from marmosets and cynomolgus monkeys showed greatly higher values than those of humans. Ebastine hydroxylation activities by marmoset and cynomolgus monkey small intestine microsomes were inhibited (approximately 60%) by anti-P450 4F antibodies, unlike human small intestine microsomes, suggesting that contribution of P450 4F enzymes for ebastine hydroxylation in the small intestine might be different between marmosets/ cynomolgus monkeys and humans. These results indicated that marmoset P450 4F2, 4F3B, 4F11, and 4F12 were expressed in livers and/or small intestines and were functional in the metabolism of endogenous and exogenous compounds, similar to those of cynomolgus monkeys and humans.

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“…To date, several isoforms have been described in the literature: CYP4F2 (15), CYP4F3A/3B (16), CYP4F8 (17,18), CYP4F11 (19,20), CYP4F12 (21), and CYP4F22 (22), corresponding to six genes that cluster to chromosome 19. CYP4F3A/3B enzymes result from an alternative splicing of the CYP4F3 gene (16).…”

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confidence: 99%

Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism

Fer

Corcos

Dréano

et al. 2008

Journal of Lipid Research

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Human CYP450 v-hydroxylases of the CYP4 family are known to convert arachidonic acid (AA) to its metabolite . This study deals with hydroxylations of four PUFAs, eicosatrienoic acid (ETA), AA, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) by either human recombinant CYP4s enzymes or human liver microsomal preparations. CYP4F3A and CYP4F3B were the most efficient v-hydroxylases of these PUFAs. Moreover, the differences in the number of unsaturations of ETA, AA, and EPA allowed us to demonstrate a rise in the metabolic rate of hydroxylation when the double bond in 14-15 or 17-18 was missing. With the CYP4F enzymes, the main pathway was always the v-hydroxylation of PUFAs, whereas it was the (v-1)-hydroxylation with CYP1A1, CYP2C19, and CYP2E1. Finally, we demonstrated that the v9 and v3 PUFAs (ETA, EPA, and DHA) could all be used as alternative substrates in AA metabolism by human CYP4F2 and -4F3B. Thus, they decreased the ability of these enzymes to convert AA to 20-HETE. However, although ETA was the most hydroxylated substrate, EPA and DHA were the most potent inhibitors of the conversion of AA to 20-HETE. These findings suggest that some physiological effects of v3 FAs could partly result from a shift in the generation of active hydroxylated metabolites of AA through a CYP-mediated catalysis.-Fer, M., L. Corcos, Y. Dréano, E. Plée-Gautier, J-P. Salaün, F. Berthou, and Y. Amet. Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism. J. Lipid Res. 2008Res. . 49: 2379Res. -2389

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Identification of CYP4F8 in Human Seminal Vesicles as a Prominent 19-Hydroxylase of Prostaglandin Endoperoxides

Cited by 76 publications

References 35 publications

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

The CYP4A Isoforms Hydroxylate Epoxyeicosatrienoic Acids to Form High Affinity Peroxisome Proliferator-activated Receptor Ligands

A New Marmoset P450 4F12 Enzyme Expressed in Small Intestines and Livers Efficiently Metabolizes Antihistaminic Drug Ebastine

Cytochromes P450 from family 4 are the main omega hydroxylating enzymes in humans: CYP4F3B is the prominent player in PUFA metabolism

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