Analysis of the cytotoxic properties of linoleic acid metabolites produced by renal and hepatic P450s.
Cytochrome P450 epoxidation of linoleic acid produces biologically active metabolites which have been associated with many pathological conditions that often lead to acute renal failure. In the present study, we evaluated the ability of specific cytochrome P450s to produce linoleic acid monoepoxides. We then tested the cytotoxic properties of linoleic acid, linoleic acid monoepoxides, and corresponding diols in a rabbit renal proximal tubule model. CYP1A2, CYP2E1, CYP2J2, CYP2J3, CYP2J5, and CYP2J9 metabolized linoleic acid at rates comparable to arachidonic acid and produced linoleic acid monoepoxides as major products. Cytotoxicity studies showed that linoleic acid, linoleic acid monoepoxides, and corresponding diols are toxic at pathologically relevant concentrations (100-500 microM). Concentration-dependent studies showed that linoleic acid and linoleic acid monoepoxides are the most toxic and induce mitochondrial dysfunction prior to cell death. Cytoprotectants known to block cell death associated with mitochondrial dysfunction and oxidative stress did not prevent cell death induced by linoleic acid and linoleic acid monoepoxides. This study shows that P450s in the CYP1 and CYP2 gene families metabolize linoleic acid to linoleic acid monoepoxides and that the monoepoxides, as well as linoleic acid, disrupt mitochondrial function without causing oxidative stress.
Moran
J H
JH
Department of Pharmacology and Toxicology, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Mitchell
L A
LA
Bradbury
J A
JA
Qu
W
W
Zeldin
D C
DC
Schnellmann
R G
RG
Grant
D F
DF
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000302:isolation & purification / Q000378:metabolism*; D004852:Epoxy Compounds / Q000378:metabolism / Q000633:toxicity; D005260:Female; D007668:Kidney / Q000201:enzymology*; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000201:enzymology; D019787:Linoleic Acid / Q000378:metabolism / Q000633:toxicity*; D008099:Liver / Q000201:enzymology*; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000378:metabolism
D004852:Epoxy Compounds; D011994:Recombinant Proteins; D003577:Cytochrome P-450 Enzyme System; D019787:Linoleic Acid