Changes in erythrocyte membrane epoxyeicosatrienoic, dihydroxyeicosatrienoic, and hydroxyeicosatetraenoic acids during pregnancy

Abstract

Aims: Pregnancy is associated with numerous changes in physiological and metabolic processes to ensure successful progression to full term. One such change is the alteration of arachidonic acid (AA) metabolism and formation of eicosanoids. This study explores the changes in AA metabolites formed through the cytochrome P450 mediated pathway to epoxyeicosatrienoic (EET), dihydroxyeicosatrienoic (DHET), and hydroxyeicosatetraenoic (HETE) acids which have been implicated in blood pressure regulation and inflammatory responses that are important for a healthy pregnancy.

Main methods: The study determines circulating levels of EETs, DHETs and HETEs extracted from erythrocyte membranes and measured by mass spectroscopy during the progression of a normal pregnancy. Blood samples, from 25 women, were collected at three time points including 25-28 weeks gestation, 28-32 weeks gestation, and the non-pregnant control at 3-4 months postpartum.

Key findings: Results demonstrate that healthy pregnancy is associated with significant increases in 8,9-DHET, 11,12-DHET and 14,15-DHET and a decrease in trans 8,9-EET during 28-32 weeks gestation compared to 3-4 months postpartum. These differences are likely due to several mechanisms including an increase in soluble epoxide hydrolase activity, a decrease in glutathione conjugation, and altered cytochrome P450 enzyme expression and/or activity that occurs during pregnancy.

Significance: Metabolism of AA through the cytochrome P450 pathway generates physiologically important eicosanoids that could play an important role in the progression of a healthy pregnancy. Establishing the changes that occur during normal pregnancy may, in the future, help in early detection of pregnancy complications including preeclampsia.

Keywords: Arachidonic acid; Dihydroxyeicosatrienoic acid; Epoxyeicosatrienoic acid; Hydroxyeicosatetraenoic acid; Pregnancy; Soluble epoxide hydrolase.

Conflict of interest statement

Conflict of Interest Statement

The authors declare that there are no conflicts of interest.

Copyright © 2020 Elsevier Inc. All rights reserved.

Figures

Figure 1.

Mean normalized EET acid content in 25-28 weeks gestation, 28-32 weeks gestation and postpartum. Blue bars depict 25-28 weeks gestation, orange bars 28-32 weeks gestation, and gray bars ≥ 3 months postpartum with each woman serving as her own control. Error bars represent standard deviations and p value

Figure 2.

Mean normalized DHET acid content in 25-28 weeks gestation, 28-32 weeks gestation and postpartum. Blue bars depict 25-28 weeks gestation, orange bars 28-32 weeks gestation, and gray bars ≥ 3 months postpartum with each woman serving as her own control. Error bars represent standard deviations and p value

Figure 3.

Mean normalized trans-EET acid content in 25-28 weeks gestation, 28-32 weeks gestation and postpartum. Blue bars depict 25-28 weeks gestation, orange bars 28-32 weeks gestation, and gray bars ≥ 3 months postpartum with each woman serving as her own control. Error bars represent standard deviations and p value < 0.05 were considered significant. Significant values are indicated with an asterisk.

Figure 4.

Mean normalized HETE acid content in 25-28 weeks gestation, 28-32 weeks gestation and postpartum. Nineteen and 20 HETE are not shown as they were below detection quantification limits. Blue bars depict 25-28 weeks gestation, orange bars 28-32 weeks gestation, and gray bars ≥ 3 months postpartum with each woman serving as her own control. Error bars represent standard deviations and p value

Figure 5.. Effects of late pregnancy on the Arachidonic Acid Cascade.

This figure depicts the release of arachidonic acid from the phospholipid membrane, followed by the various pathways for AA metabolism. Lipoxygenases are involved in the formation of the hydroxyeicosatetraenoic acids. Cyclooxygenases are involved in the formation of the prostaglandins and thromboxanes. Reactive oxygen species are involved in the formation of the trans-epoxyeicosatrienoic acids. CytochromeP450 enzymes are involved in the formation of the cis-epoxyeicosatrienoic acids and two of the hydroxyeicosatetraenoic acids. The cis-epoxyeicosatrienoic acids undergo further metabolism by soluble epoxide hydrolase to the dihydroxyeicosatrienoic acids, which are either excreted in the urine or undergo conjugation with glutathione prior to excretion. The cis-epoxyeicosatrienoic acids can also undergo re-esterification via acyl CoA and return to the phospholipid membrane. The green arrows indicate the compounds in which a statistically significant differences (p