{Omega}-oxidation of {alpha}-chlorinated fatty acids: identification of {alpha}-chlorinated dicarboxylic acids.
Myeloperoxidase-derived HOCl targets tissue- and lipoprotein-associated plasmalogens to generate α-chlorinated fatty aldehydes, including 2-chlorohexadecanal. Under physiological conditions, 2-chlorohexadecanal is oxidized to 2-chlorohexadecanoic acid (2-ClHA). This study demonstrates the catabolism of 2-ClHA by ω-oxidation and subsequent β-oxidation from the ω-end. Mass spectrometric analyses revealed that 2-ClHA is ω-oxidized in the presence of liver microsomes with initial ω-hydroxylation of 2-ClHA. Subsequent oxidation steps were examined in a human hepatocellular cell line (HepG2). Three different α-chlorinated dicarboxylic acids, 2-chlorohexadecane-(1,16)-dioic acid, 2-chlorotetradecane-(1,14)-dioic acid, and 2-chloroadipic acid (2-ClAdA), were identified. Levels of 2-chlorohexadecane-(1,16)-dioic acid, 2-chlorotetradecane-(1,14)-dioic acid, and 2-ClAdA produced by HepG2 cells were dependent on the concentration of 2-ClHA and the incubation time. Synthetic stable isotope-labeled 2-ClHA was used to demonstrate a precursor-product relationship between 2-ClHA and the α-chlorinated dicarboxylic acids. We also report the identification of endogenous 2-ClAdA in human and rat urine and elevations in stable isotope-labeled urinary 2-ClAdA in rats subjected to intraperitoneal administration of stable isotope-labeled 2-ClHA. Furthermore, urinary 2-ClAdA and plasma 2-ClHA levels are increased in LPS-treated rats. Taken together, these data show that 2-ClHA is ω-oxidized to generate α-chlorinated dicarboxylic acids, which include α-chloroadipic acid that is excreted in the urine.
Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St Louis, Missouri 63104, USA.
Viral V
VV
Brahmbhatt
Carolyn J
CJ
Albert
Dhanalakshmi S
DS
Anbukumar
Bryce A
BA
Cunningham
William L
WL
Neumann
David A
DA
Ford
D000818:Animals; D002713:Chlorine / Q000737:chemistry*; D003998:Dicarboxylic Acids / Q000737:chemistry* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000166:cytology; D006801:Humans; D013058:Mass Spectrometry / Q000379:methods; D008862:Microsomes, Liver / Q000378:metabolism; D010100:Oxygen / Q000737:chemistry; D010169:Palmitic Acids / Q000737:chemistry; D009195:Peroxidase / Q000737:chemistry; D010544:Peroxidases / Q000737:chemistry; D011817:Rabbits; D051381:Rats
C532464:2-chlorohexadecanoic acid; D003998:Dicarboxylic Acids; D005227:Fatty Acids; D010169:Palmitic Acids; D002713:Chlorine; D010544:Peroxidases; D009195:Peroxidase; D010100:Oxygen