Regulation of arachidonic acid metabolism by cytochrome P-450 in rabbit kidney

Renal microsomal cytochrome P-450-dependent arachidonic acid metabolism was correlated with the level of cytochrome P-450 in the rabbit kidney. Cobalt, an inducer of haem oxygenase, reduced cytochrome P-450 in both the cortex and medulla in association with a 2-fold decrease in aryl-hydrocarbon hydroxylase, an index of cytochrome P-450 activity, and a similar decrease in the formation of cytochrome P-450-dependent arachidonic acid metabolites by renal microsomes (microsomal fractions). Formation of the latter was absolutely dependent on NADPH addition and was prevented by SKF-525A, an inhibitor of cytochrome P-450-dependent enzymes. Arachidonate metabolites of cortical microsomes were identified by g.c.-m.s. as 20- and 19-hydroxyeicosatetraenoic acid, 11,12-epoxyeicosatrienoic acid and 11,12-dihydroxyeicosatrienoic acid. The profile of arachidonic acid metabolites was the same for the medullary microsomes. Induction of cytochrome P-450 by 3-methylcholanthrene and beta-naphthoflavone increased cytochrome P-450 content and aryl-hydrocarbon hydroxylase activity by 2-fold in the cortex and medulla, and this correlated with a 2-fold increase in arachidonic acid metabolites via the cytochrome P-450 pathway. These changes can also be demonstrated in cells isolated from the medullary segment of the thick ascending limb of the loop of Henle, which previously have been shown to metabolize arachidonic acid specifically via the cytochrome P-450-dependent pathway. The specific activity for the formation of arachidonic acid metabolites by this pathway is higher in the kidney than in the liver, the highest activity being in the outer medulla, namely 7.9 microgram as against 2.5 micrograms of arachidonic acid transformed/30 min per nmol of cytochrome P-450 for microsomes obtained from outer medulla and liver respectively. These findings are consistent with high levels of cytochrome P-450 isoenzyme(s), specific for arachidonic acid metabolism, primarily localized in the outer medulla.

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Metformin Affects Cardiac Arachidonic Acid Metabolism and Cardiac Lipid Metabolite Storage in a Prediabetic Rat Model

International Journal of Molecular Sciences ◽

10.3390/ijms22147680 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7680

Author(s):

Denisa Miklankova ◽

Irena Markova ◽

Martina Hüttl ◽

Iveta Zapletalova ◽

Martin Poruba ◽

...

Keyword(s):

Gene Expression ◽

Arachidonic Acid ◽

Fatty Acid ◽

Rat Model ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Phospholipid Fatty Acid Composition ◽

Metformin Treatment ◽

Arachidonic Acid Metabolites ◽

Acid Metabolites

Metformin can reduce cardiovascular risk independent of glycemic control. The mechanisms behind its non-glycemic benefits, which include decreased energy intake, lower blood pressure and improved lipid and fatty acid metabolism, are not fully understood. In our study, metformin treatment reduced myocardial accumulation of neutral lipids—triglycerides, cholesteryl esters and the lipotoxic intermediates—diacylglycerols and lysophosphatidylcholines in a prediabetic rat model (p < 0.001). We observed an association between decreased gene expression and SCD-1 activity (p < 0.05). In addition, metformin markedly improved phospholipid fatty acid composition in the myocardium, represented by decreased SFA profiles and increased n3-PUFA profiles. Known for its cardioprotective and anti-inflammatory properties, metformin also had positive effects on arachidonic acid metabolism and CYP-derived arachidonic acid metabolites. We also found an association between increased gene expression of the cardiac isoform CYP2c with increased 14,15-EET (p < 0.05) and markedly reduced 20-HETE (p < 0.001) in the myocardium. Based on these results, we conclude that metformin treatment reduces the lipogenic enzyme SCD-1 and the accumulation of the lipotoxic intermediates diacylglycerols and lysophosphatidylcholine. Increased CYP2c gene expression and beneficial effects on CYP-derived arachidonic acid metabolites in the myocardium can also be involved in cardioprotective effect of metformin.

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THE VARIATION OF ARACHIDONIC ACID METABOLISM OF PMN LEUKOCYTES IN CEREBRAL THROMBOSIS

10.1055/s-0038-1643155 ◽

1987 ◽

Author(s):

Z Wang ◽

B Lehuu ◽

Y He ◽

C Raun

Keyword(s):

Arachidonic Acid ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Cerebral Thrombosis ◽

Potent Inducer ◽

Tissue Ischemia ◽

Significant Difference ◽

Arachidonic Acid Metabolites ◽

Pmn Leukocytes ◽

Acid Metabolites

It was suggested that there is a transfer of metabolites between leukocytes,paltelets and endothelial cells,and that the leukocytes might take part in thrombosis and haemostasis. In order to ascertain whether the arachidonic acid metabolism of PMN leukocytes changes when cerebral thrombosis occurs, we studied this metabolism using isolated human PMN leukocytes, stimulated by ionophor A23187. PGE2 and TXB2 were measured with the method of radioimmunoassay, while leukotrienes(LT) were separated and measured by HPLC. The amount of PGE2, TXB2 and LTs produced by PMN leukocytes of 8 normal volunteers was compared with that of 8 patients suffering from cerebral thrombosis. All these patients were confirmed by CT examination. We found that the production of TXB2, LTB4 and its derivative 20-0H-LTB4 of PMN leukocytes of patients was significantly enhanced. The PGE2 production of PMN leukocytes of patients was also higher than that 0? the volunteers, but without statistically significant difference.These results demonstrate that leukocytes and their arachi donic acid metabolites might play some role in the pathogenetic sequence of cerebral thrombosis. And it is possible that LTB4 is not only a potent inducer of neutrophil chemotaxis and leukocyte aggregation, but also an associated factor in the ischemic vascular disease. It seems that the increasing production of TXB2 and LTB4 by PMN leukocytes is not the main reason of cerebral thrombosis. Hoever, it might accelerate the degree of brain tissue ischemia. We observed that corticosteroids, as an inhibitor of phosphoIipase A2,strikingly reduced the production of arachidonic acid metabolites by leukocytes. Therefore, it is probable that the efficacy of corticosteroids on cerebral thrombosis is, in part, due to inhibit the production of these arachidonic acid metabolites of leukocytes.

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Inhibition of renal arachidonic acid ω-hydroxylase activity with ABT reduces blood pressure in the SHR

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1998.275.2.r426 ◽

1998 ◽

Vol 275 (2) ◽

pp. R426-R438 ◽

Cited By ~ 49

Author(s):

Ping Su ◽

K. Maya Kaushal ◽

Deanna L. Kroetz

Keyword(s):

Blood Pressure ◽

Arachidonic Acid ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Sprague Dawley ◽

Hydroxylase Activity ◽

Outer Medulla ◽

Spontaneously Hypertensive ◽

Protein Levels ◽

Intraperitoneal Dose

The mechanism-based cytochrome P-450 (CYP) inhibitor 1-aminobenzotriazole (ABT) was characterized as an inhibitor of renal arachidonic acid metabolism and administered to spontaneously hypertensive rats (SHRs) to determine the effect of reduced eicosanoid production on mean arterial pressure (MAP). A single intraperitoneal dose of ABT to Sprague-Dawley rats caused a dose-dependent loss of renal CYP content, arachidonic acid metabolism, and CYP4A protein. In the cortex and outer medulla, ABT showed a high degree of selectivity for the CYP4A enzymes, reflected by the potent inhibition of 19- and 20-hydroxyeicosatetraenoic acid (19- and 20-HETE) formation. A 50 mg/kg dose of ABT reduced cortical 20-HETE formation to 16.1 ± 0.82% of control and outer medullary 20-HETE formation to 23.8 ± 0.45% of control. In contrast, there was no inhibition of renal epoxygenase activity at this dose. Renal CYP content, arachidonic acid ω- and (ω-1)-hydroxylase activity, and CYP4A protein levels gradually return to control levels by 72 h after a single dose of ABT. Cortical 20-HETE formation recovered from 17.9 ± 3.15% of control at 6 h to 84.8 ± 4.67% of control at 72 h after ABT administration. A single injection of ABT to 7-wk-old SHRs caused an acute reduction in MAP, which remained suppressed for at least 12 h. The effect was maximal within 4 h and averaged 17–23 mmHg during the 4- to 12-h period after administration. 20-HETE formation was inhibited 85% in the cortex and 70–80% in the outer medulla during the period when MAP was reduced. A structurally related ABT analog 1-hydroxybenzotriazole had no effect on blood pressure or renal arachidonic acid metabolism. These results identify ABT as a selective inhibitor of renal CYP4A activity and provide further support for a role for 20-HETE in the regulation of blood pressure.

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ChemInform Abstract: SYNTHESIS OF ARACHIDONIC ACID METABOLITES PRODUCED BY PURIFIED KIDNEY CORTEX MICROSOMAL CYTOCHROME P-450

Chemischer Informationsdienst ◽

10.1002/chin.198319136 ◽

1983 ◽

Vol 14 (19) ◽

Author(s):

S. MANNA ◽

J. R. FALCK ◽

N. CHACOS ◽

J. CAPDEVILA

Keyword(s):

Arachidonic Acid ◽

Kidney Cortex ◽

Microsomal Cytochrome ◽

Arachidonic Acid Metabolites ◽

Acid Metabolites ◽

Cytochrome P 450

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Lipoxygenase-dependent superoxide release in skeletal muscle

Journal of Applied Physiology ◽

10.1152/japplphysiol.00096.2004 ◽

2004 ◽

Vol 97 (2) ◽

pp. 661-668 ◽

Cited By ~ 74

Author(s):

Li Zuo ◽

Fievos L. Christofi ◽

Valerie P. Wright ◽

Shengying Bao ◽

Thomas L. Clanton

Keyword(s):

Skeletal Muscle ◽

Arachidonic Acid ◽

Cytochrome C ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

Anion Channels ◽

Cytochrome C Reduction ◽

First Time ◽

Cytochrome P 450 ◽

Different Sources

Superoxide anion radical (O2•−) is released from skeletal muscle at rest and is particularly elevated during conditions of heat stress (42°C). Previous studies have shown that in isolated rat diaphragm O2•− release is not dependent on mitochondrial electron transport, reduced NADP oxidase activity, or the integrity of membrane anion channels. This study hypothesized that O2•− release, as measured by cytochrome c reduction, is linked to metabolism of arachidonic acid. Phospholipase A2 inhibition with manoalide significantly decreased O2•− release. In downstream pathways, neither the blockage of cyclooxygenase with indomethacin nor the inhibition of cytochrome P-450-dependent monooxygenase with SKF-525A decreased O2•− release. However, lipoxygenase (LOX) inhibition with general LOX blockers 5,8,11,14-eicosatetraynoic acid and cinnamyl-3,4-dihydroxy-α-cyanocinnamate greatly attenuated the signal. Furthermore, the specific 5-LOX inhibitor diethylcarbamazine also significantly decreased O2•− release. Immunohistochemistry localized 5- and 12-LOX to the cytosol and sarcolemma of muscle cells. Confocal studies, using the O2•−-sensitive fluorescent indicator hydroethidine, demonstrated that LOX inhibition had no significant influence on intracellular O2•− formation. When compared with the cytochrome c results, this indicates that intra- and extracellular O2•− must arise from different sources. These data show for the first time that arachidonic acid metabolism through LOX activity, is a major source of extracellular O2•− release in skeletal muscle.

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Role of cytochrome P-450 4A in oxygen sensing and NO production in rat cremaster resistance arteries

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.4.h1546 ◽

1999 ◽

Vol 277 (4) ◽

pp. H1546-H1552 ◽

Cited By ~ 14

Author(s):

Cornel J. M. Kerkhof ◽

Erik N. T. P. Bakker ◽

Pieter Sipkema

Keyword(s):

Arachidonic Acid ◽

Acid Metabolism ◽

Arachidonic Acid Metabolism ◽

No Production ◽

Cremaster Muscle ◽

Resistance Arteries ◽

Arterial Diameter ◽

Spontaneous Tone ◽

Cytochrome P 450

The role of arachidonic acid metabolism and nitric oxide (NO) in hypoxia-induced changes of vascular tone was investigated in first-order cannulated rat cremaster muscle resistance arteries. Spontaneous tone reduced arterial diameter from 179 ± 2 μm (fully dilated) to 98 ± 3 μm under normoxia ([Formula: see text] = 150 mmHg). Hypoxia ([Formula: see text] 5–10 mmHg) had no significant effect on arterial diameter under conditions of spontaneous tone. The effect of hypoxia was not changed after blockade of cyclooxygenase with indomethacin or after blockade of lipoxygenase with nordihydroguaiaretic acid. However, after partial blockade of cytochrome P-450 4A enzymes with 17-octadecynoic acid (17-ODYA), hypoxia increased the diameter by 65 ± 6 μm ( P < 0.05). This increase could be inhibited by N G-nitro-l-arginine (l-NNA) or 20-hydroxyeicosatetraenoic acid (20-HETE). 17-ODYA induced a concentration-dependent dilation under normoxia, which could be blocked by endothelium removal orl-NNA. 17-ODYA did not increase smooth muscle sensitivity to NO. We conclude that, under conditions of spontaneous tone and in the absence of luminal flow, hypoxia (5–10 mmHg) has no effect on the diameter of resistance arteries from the rat cremaster muscle. Inhibition of the cytochrome P-450 4A pathway of arachidonic acid metabolism under normoxia induces NO production by the endothelium. Hypoxia induces an NO-mediated dilation when cytochrome P-450 4A enzymes are partially inhibited.

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