CYP enzymes catalyze the formation of a terminal olefin from 2-ethylhexanoic acid in rat and human liver.
1. The metabolism of 2-ethylhexanoic acid (2-EHA) was studied in rat, mouse and human liver microsomes in vitro. The metabolites of 2-EHA were identified as methylated derivatives by gas chromatography-mass spectrometry. 2. 2-Ethyl-1,6-hexanedioic acid was the main metabolite produced in rat, mouse and human liver microsomes. Unsaturated 2-ethyl-5-hexenoic acid, a terminal olefin, was produced only in human liver microsomes and phenobarbital-induced rat liver microsomes. The cytochrome P450 (CYP) inhibitors metyrapone, SKF 525A, triacetyloleandomycin (TAO), quinidine and the cytochrome P450 reductase antibody abolished its formation both in rat and human microsomes. 3. The metabolites were analyzed also in vivo in urine of 2-EHA-exposed rats and in urine of sawmill workers exposed occupationally to 2-EHA. Both rat and human urine contained 2-ethyl-1,6-hexanedioic acid as the main metabolite and also 2-ethyl-5-hexenoic acid. Metyrapone, SKF 525A and TAO all decreased drastically the formation of 2-ethyl-5-hexenoic acid in the rat. 4. The data indicate that (1) several CYP families (CYP2A, CYP2B, CYP2D and CYP3A) could be responsible for the hepatic metabolism of 2-EHA, (2) the same metabolites were formed in rats and man and (3) an unsaturated terminal olefin, 2-ethyl-5-hexenoic acid is formed in the liver.
Pennanen
S
S
National Public Health Institute, Division of Environmental Health, Kuopio, Finland.
Kojo
A
A
Pasanen
M
M
Liesivuori
J
J
Juvonen
R O
RO
Komulainen
H
H
D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002208:Caproates / Q000378:metabolism / Q000633:toxicity* / Q000652:urine; D065607:Cytochrome P-450 Enzyme Inhibitors; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007527:Isoenzymes; D008297:Male; D008745:Methylation; D008797:Metyrapone / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects* / Q000378:metabolism; D008875:Middle Aged; D009251:NADPH-Ferrihemoprotein Reductase / Q000276:immunology; D016273:Occupational Exposure; D011335:Proadifen / Q000494:pharmacology; D011802:Quinidine / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D014217:Troleandomycin / Q000008:administration & dosage / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D002208:Caproates; D065607:Cytochrome P-450 Enzyme Inhibitors; D007527:Isoenzymes; C040668:2-ethylhexanoic acid; D011335:Proadifen; D014217:Troleandomycin; D009251:NADPH-Ferrihemoprotein Reductase; D011802:Quinidine; D008797:Metyrapone