Kinetic profile of the rat CYP4A isoforms: Arachidonic acid metabolism and isoform-specific inhibitors

Xuandai Nguyen, Mong-Heng Wang, Komandla M. Reddy, John R. Falck, Michal Laniado Schwartzman

Research output: Contribution to journalArticle

150 Citations (Scopus)

Abstract

20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome P-450 (CYP) 4A ω-hydroxylation product of arachidonic acid, has potent biological effects on renal tubular and vascular functions and on the control of arterial pressure. We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and - 4A8 cDNAs, using baculovirus and Sf9 insect cells. Arachidonic acid ω- and ω-1-hydroxylations were catalyzed by three of the CYP4A isoforms; the highest catalytic efficiency of 947 nM-1 · min-+ for CYP4A1 was followed by 72 and 22 nM-1 · min-1 for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3 exhibited an additional arachidonate 11,12-epoxidation activity, whereas CYP4A1 operated solely as an ω-hydroxylase. CYP4A8 did not catalyze arachidonic or linoleic acid but did have a detectable lauric acid ω- hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and indicated isoform- specific inhibition. These studies suggest that CYP4A1, despite its low expression in extrahepatic tissues, may constitute the major source of 20- HETE synthesis. Moreover, the ability of CYP4A2 and -4A3 to catalyze the formation of two opposing biologically active metabolites, 20-HETE and 11,12- epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Volume276
Issue number6 45-6
StatePublished - Jan 1 1999

Fingerprint

Cytochrome P-450 CYP4A
Hydroxylation
Arachidonic Acid
Protein Isoforms
lauric acid
Blood Vessels
Sf9 Cells
Baculoviridae
Linoleic Acid
Mixed Function Oxygenases
Insects
Arterial Pressure
Fatty Acids
Complementary DNA
Kidney
cytochrome P-450 CYP4A2 (rat)
20-hydroxy-5,8,11,14-eicosatetraenoic acid

Keywords

  • 12- epoxyeicosatrienoic acid
  • 20-hydroxyeicosatetraenoic acid 11
  • Fatty acid ω-hydroxylation

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

Cite this

Kinetic profile of the rat CYP4A isoforms : Arachidonic acid metabolism and isoform-specific inhibitors. / Nguyen, Xuandai; Wang, Mong-Heng; Reddy, Komandla M.; Falck, John R.; Schwartzman, Michal Laniado.

In: American Journal of Physiology - Regulatory Integrative and Comparative Physiology, Vol. 276, No. 6 45-6, 01.01.1999.

Research output: Contribution to journalArticle

@article{d42d168f8bdf44a4abb4781d2c38d311,
title = "Kinetic profile of the rat CYP4A isoforms: Arachidonic acid metabolism and isoform-specific inhibitors",
abstract = "20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome P-450 (CYP) 4A ω-hydroxylation product of arachidonic acid, has potent biological effects on renal tubular and vascular functions and on the control of arterial pressure. We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and - 4A8 cDNAs, using baculovirus and Sf9 insect cells. Arachidonic acid ω- and ω-1-hydroxylations were catalyzed by three of the CYP4A isoforms; the highest catalytic efficiency of 947 nM-1 · min-+ for CYP4A1 was followed by 72 and 22 nM-1 · min-1 for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3 exhibited an additional arachidonate 11,12-epoxidation activity, whereas CYP4A1 operated solely as an ω-hydroxylase. CYP4A8 did not catalyze arachidonic or linoleic acid but did have a detectable lauric acid ω- hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and indicated isoform- specific inhibition. These studies suggest that CYP4A1, despite its low expression in extrahepatic tissues, may constitute the major source of 20- HETE synthesis. Moreover, the ability of CYP4A2 and -4A3 to catalyze the formation of two opposing biologically active metabolites, 20-HETE and 11,12- epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone.",
keywords = "12- epoxyeicosatrienoic acid, 20-hydroxyeicosatetraenoic acid 11, Fatty acid ω-hydroxylation",
author = "Xuandai Nguyen and Mong-Heng Wang and Reddy, {Komandla M.} and Falck, {John R.} and Schwartzman, {Michal Laniado}",
year = "1999",
month = "1",
day = "1",
language = "English (US)",
volume = "276",
journal = "American Journal of Physiology - Heart and Circulatory Physiology",
issn = "0363-6135",
publisher = "American Physiological Society",
number = "6 45-6",

}

TY - JOUR

T1 - Kinetic profile of the rat CYP4A isoforms

T2 - Arachidonic acid metabolism and isoform-specific inhibitors

AU - Nguyen, Xuandai

AU - Wang, Mong-Heng

AU - Reddy, Komandla M.

AU - Falck, John R.

AU - Schwartzman, Michal Laniado

PY - 1999/1/1

Y1 - 1999/1/1

N2 - 20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome P-450 (CYP) 4A ω-hydroxylation product of arachidonic acid, has potent biological effects on renal tubular and vascular functions and on the control of arterial pressure. We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and - 4A8 cDNAs, using baculovirus and Sf9 insect cells. Arachidonic acid ω- and ω-1-hydroxylations were catalyzed by three of the CYP4A isoforms; the highest catalytic efficiency of 947 nM-1 · min-+ for CYP4A1 was followed by 72 and 22 nM-1 · min-1 for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3 exhibited an additional arachidonate 11,12-epoxidation activity, whereas CYP4A1 operated solely as an ω-hydroxylase. CYP4A8 did not catalyze arachidonic or linoleic acid but did have a detectable lauric acid ω- hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and indicated isoform- specific inhibition. These studies suggest that CYP4A1, despite its low expression in extrahepatic tissues, may constitute the major source of 20- HETE synthesis. Moreover, the ability of CYP4A2 and -4A3 to catalyze the formation of two opposing biologically active metabolites, 20-HETE and 11,12- epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone.

AB - 20-Hydroxyeicosatetraenoic acid (HETE), the cytochrome P-450 (CYP) 4A ω-hydroxylation product of arachidonic acid, has potent biological effects on renal tubular and vascular functions and on the control of arterial pressure. We have expressed high levels of the rat CYP4A1, -4A2, -4A3, and - 4A8 cDNAs, using baculovirus and Sf9 insect cells. Arachidonic acid ω- and ω-1-hydroxylations were catalyzed by three of the CYP4A isoforms; the highest catalytic efficiency of 947 nM-1 · min-+ for CYP4A1 was followed by 72 and 22 nM-1 · min-1 for CYP4A2 and CYP4A3, respectively. CYP4A2 and CYP4A3 exhibited an additional arachidonate 11,12-epoxidation activity, whereas CYP4A1 operated solely as an ω-hydroxylase. CYP4A8 did not catalyze arachidonic or linoleic acid but did have a detectable lauric acid ω- hydroxylation activity. The inhibitory activity of various acetylenic and olefinic fatty acid analogs revealed differences and indicated isoform- specific inhibition. These studies suggest that CYP4A1, despite its low expression in extrahepatic tissues, may constitute the major source of 20- HETE synthesis. Moreover, the ability of CYP4A2 and -4A3 to catalyze the formation of two opposing biologically active metabolites, 20-HETE and 11,12- epoxyeicosatrienoic acid, may be of great significance to the regulation of vascular tone.

KW - 12- epoxyeicosatrienoic acid

KW - 20-hydroxyeicosatetraenoic acid 11

KW - Fatty acid ω-hydroxylation

UR - http://www.scopus.com/inward/record.url?scp=0032997280&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0032997280&partnerID=8YFLogxK

M3 - Article

C2 - 10362749

AN - SCOPUS:0032997280

VL - 276

JO - American Journal of Physiology - Heart and Circulatory Physiology

JF - American Journal of Physiology - Heart and Circulatory Physiology

SN - 0363-6135

IS - 6 45-6

ER -