Urinary prostaglandin F2α is generated from the isoprostane pathway and not the cyclooxygenase in humans

Huiyong Yin; Ling Gao; Hsin-Hsiung Tai; Laine J. Murphey; Ned A. Porter; Jason D. Morrow

doi:10.1074/jbc.M608975200

Urinary prostaglandin F_2α is generated from the isoprostane pathway and not the cyclooxygenase in humans

Huiyong Yin, Ling Gao, Hsin-Hsiung Tai, Laine J. Murphey, Ned A. Porter, Jason D. Morrow

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

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Abstract

Prostaglandins (PGs) derived from the enzymatic oxidation of arachidonic acid by the cyclooxygenases (COXs) are potent lipid mediators involved in human physiology and pathophysiology. Structurally similar compounds, the isoprostanes (IsoPs), are generated from the free radical-catalyzed oxidation of arachidonic acid independent of COX. IsoPs exhibit significant bioactivity and play a role in the pathogenesis of diseases associated with oxidant injury. As one of the major PGs, prostaglandin F_2α(PGF_2α) is present in human urine in significant concentrations and is presumed to be derived from COX activity. We determined, however, that levels of putative PGF _2α in urine cannot be suppressed by nonsteroidal anti-inflammatory agents, suggesting that it is generated via another mechanism(s). An important difference between COX-derived PGF_2α and the IsoPs is that the former is an optically pure compound, whereas IsoPs are racemic. Utilizing a rodent model of oxidative stress, we now show that significant amounts of compounds identical in all respects to PGF _2α and its enantiomer, ent-PGF_2α, are formed in equal amounts esterified in tissue phospholipids, suggesting that these compounds are derived via the IsoP pathway. Further, employing liquid chromatography/mass spectrometry, the vast majority of putative PGF _2α in human urine is derived from the free radical-initiated peroxidation of arachidonate independent of COX and is composed of PGF _2α and its enantiomer, although the latter compound is ∼2-fold more abundant. Thus, quantification of urinary PGF _2α actually reflects oxidative stress status as opposed to COX activity. Indeed, levels of this compound are elevated in urine from cigarette smokers and in humans with hypercholesterolemia, two conditions associated with oxidant stress. The elucidation that urinary PGF_2α in humans is derived from the IsoP pathway has implications regarding PG formation and inhibition in vivo. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

Original language	English
Pages (from-to)	329-336
Journal	Journal of Biological Chemistry
Volume	282
Issue number	1
DOIs	https://doi.org/10.1074/jbc.M608975200
Publication status	Published - 5 Jan 2007
Externally published	Yes

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title = "Urinary prostaglandin F2α is generated from the isoprostane pathway and not the cyclooxygenase in humans",

abstract = "Prostaglandins (PGs) derived from the enzymatic oxidation of arachidonic acid by the cyclooxygenases (COXs) are potent lipid mediators involved in human physiology and pathophysiology. Structurally similar compounds, the isoprostanes (IsoPs), are generated from the free radical-catalyzed oxidation of arachidonic acid independent of COX. IsoPs exhibit significant bioactivity and play a role in the pathogenesis of diseases associated with oxidant injury. As one of the major PGs, prostaglandin F2α(PGF2α) is present in human urine in significant concentrations and is presumed to be derived from COX activity. We determined, however, that levels of putative PGF 2α in urine cannot be suppressed by nonsteroidal anti-inflammatory agents, suggesting that it is generated via another mechanism(s). An important difference between COX-derived PGF2α and the IsoPs is that the former is an optically pure compound, whereas IsoPs are racemic. Utilizing a rodent model of oxidative stress, we now show that significant amounts of compounds identical in all respects to PGF 2α and its enantiomer, ent-PGF2α, are formed in equal amounts esterified in tissue phospholipids, suggesting that these compounds are derived via the IsoP pathway. Further, employing liquid chromatography/mass spectrometry, the vast majority of putative PGF 2α in human urine is derived from the free radical-initiated peroxidation of arachidonate independent of COX and is composed of PGF 2α and its enantiomer, although the latter compound is ∼2-fold more abundant. Thus, quantification of urinary PGF 2α actually reflects oxidative stress status as opposed to COX activity. Indeed, levels of this compound are elevated in urine from cigarette smokers and in humans with hypercholesterolemia, two conditions associated with oxidant stress. The elucidation that urinary PGF2α in humans is derived from the IsoP pathway has implications regarding PG formation and inhibition in vivo. {\textcopyright} 2007 by The American Society for Biochemistry and Molecular Biology, Inc.",

author = "Huiyong Yin and Ling Gao and Hsin-Hsiung Tai and Murphey, {Laine J.} and Porter, {Ned A.} and Morrow, {Jason D.}",

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T1 - Urinary prostaglandin F2α is generated from the isoprostane pathway and not the cyclooxygenase in humans

AU - Yin, Huiyong

AU - Gao, Ling

AU - Tai, Hsin-Hsiung

AU - Murphey, Laine J.

AU - Porter, Ned A.

AU - Morrow, Jason D.

N1 - Publication details (e.g. title, author(s), publication statuses and dates) are captured on an “AS IS” and “AS AVAILABLE” basis at the time of record harvesting from the data source. Suggestions for further amendments or supplementary information can be sent to [email protected].

PY - 2007/1/5

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N2 - Prostaglandins (PGs) derived from the enzymatic oxidation of arachidonic acid by the cyclooxygenases (COXs) are potent lipid mediators involved in human physiology and pathophysiology. Structurally similar compounds, the isoprostanes (IsoPs), are generated from the free radical-catalyzed oxidation of arachidonic acid independent of COX. IsoPs exhibit significant bioactivity and play a role in the pathogenesis of diseases associated with oxidant injury. As one of the major PGs, prostaglandin F2α(PGF2α) is present in human urine in significant concentrations and is presumed to be derived from COX activity. We determined, however, that levels of putative PGF 2α in urine cannot be suppressed by nonsteroidal anti-inflammatory agents, suggesting that it is generated via another mechanism(s). An important difference between COX-derived PGF2α and the IsoPs is that the former is an optically pure compound, whereas IsoPs are racemic. Utilizing a rodent model of oxidative stress, we now show that significant amounts of compounds identical in all respects to PGF 2α and its enantiomer, ent-PGF2α, are formed in equal amounts esterified in tissue phospholipids, suggesting that these compounds are derived via the IsoP pathway. Further, employing liquid chromatography/mass spectrometry, the vast majority of putative PGF 2α in human urine is derived from the free radical-initiated peroxidation of arachidonate independent of COX and is composed of PGF 2α and its enantiomer, although the latter compound is ∼2-fold more abundant. Thus, quantification of urinary PGF 2α actually reflects oxidative stress status as opposed to COX activity. Indeed, levels of this compound are elevated in urine from cigarette smokers and in humans with hypercholesterolemia, two conditions associated with oxidant stress. The elucidation that urinary PGF2α in humans is derived from the IsoP pathway has implications regarding PG formation and inhibition in vivo. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

AB - Prostaglandins (PGs) derived from the enzymatic oxidation of arachidonic acid by the cyclooxygenases (COXs) are potent lipid mediators involved in human physiology and pathophysiology. Structurally similar compounds, the isoprostanes (IsoPs), are generated from the free radical-catalyzed oxidation of arachidonic acid independent of COX. IsoPs exhibit significant bioactivity and play a role in the pathogenesis of diseases associated with oxidant injury. As one of the major PGs, prostaglandin F2α(PGF2α) is present in human urine in significant concentrations and is presumed to be derived from COX activity. We determined, however, that levels of putative PGF 2α in urine cannot be suppressed by nonsteroidal anti-inflammatory agents, suggesting that it is generated via another mechanism(s). An important difference between COX-derived PGF2α and the IsoPs is that the former is an optically pure compound, whereas IsoPs are racemic. Utilizing a rodent model of oxidative stress, we now show that significant amounts of compounds identical in all respects to PGF 2α and its enantiomer, ent-PGF2α, are formed in equal amounts esterified in tissue phospholipids, suggesting that these compounds are derived via the IsoP pathway. Further, employing liquid chromatography/mass spectrometry, the vast majority of putative PGF 2α in human urine is derived from the free radical-initiated peroxidation of arachidonate independent of COX and is composed of PGF 2α and its enantiomer, although the latter compound is ∼2-fold more abundant. Thus, quantification of urinary PGF 2α actually reflects oxidative stress status as opposed to COX activity. Indeed, levels of this compound are elevated in urine from cigarette smokers and in humans with hypercholesterolemia, two conditions associated with oxidant stress. The elucidation that urinary PGF2α in humans is derived from the IsoP pathway has implications regarding PG formation and inhibition in vivo. © 2007 by The American Society for Biochemistry and Molecular Biology, Inc.

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