In vitro hydroxylation and epoxidation of some isomeric lauric acid analogs by rat liver microsomes. Identification of metabolites and effects of clofibrate or phenobarbital pretreatment.
The primary metabolites of a series of unsaturated lauric acid analogs (8-, 9-, 10-, and 11-dodecenoic acids) used as radiolabeled substrates for rat liver microsomes were quantitated by TLC and reverse phase-HPLC analysis, and identified by chemical derivation and GC/MS. Isomeric epoxidodecanoic acids and omega- and (omega-1)-monohydroxydodecenoic acids were essentially the only products formed from the incubations of the unsaturated fatty acids. Rat liver microsomes predominantly oxidized the terminal carbons of all substrates, leading to omega- and (omega-1)-hydroxylated metabolites, with the exception of 11-dodecenoic acid, which was efficiently converted to the epoxide. The E and Z isomers of dodecenoic acids were metabolized with the same efficiency and gave rise to the same pattern of hydroxylated vs. epoxidized products. The hydroxylation/epoxidation ratio was directly related to the position, but not to the geometry of the double bond in the aliphatic chain. Clofibrate pretreatment of the animals resulted in a strong induction of omega-oxidation, with a decrease in the ability to catalyze epoxidation of internal olefins, whereas phenobarbital pretreatment only stimulated (omega-1)-hydroxylation without any effect on epoxidation. In contrast to higher plants in which carbon 9 is the major target, rat liver cytochromes P450 selectively carried out hydroxylation (or epoxidation) at carbons 12 and 11 of lauric acid, as well as its unsaturated isomeric analogs.
Boucher
J L
JL
Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, CNRS-URA 400, Paris, France.
Delaforge
M
M
Salaün
J P
JP
Pinot
F
F
Durst
F
F
Pflieger
P
P
Mioskowski
C
C
D000818:Animals; D002855:Chromatography, Thin Layer; D002994:Clofibrate / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004790:Enzyme Induction; D005229:Fatty Acids, Monounsaturated / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D007850:Lauric Acids / Q000737:chemistry / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism*; D010634:Phenobarbital / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D005229:Fatty Acids, Monounsaturated; D007850:Lauric Acids; C054728:11-dodecenoic acid; D003577:Cytochrome P-450 Enzyme System; D002994:Clofibrate; D010634:Phenobarbital