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CYP enzymes catalyze the formation of a terminal olefin from 2-ethylhexanoic acid in rat and human liver

National Public Health Institute, Division of Environmental Health, P.O.B. 95, FIN-70701 Kuopio, Finland

A. Kojo

Department of Pharmacology and Toxicology, University of Kuopio, P.O.B. 1627, FIN-70211, Kuopio, Finland

M. Pasanen

Department of Pharmacology and Toxicology, University of Kuopio, P.O.B. 1627, FIN-70211, Kuopio, Finland

J. Liesivuori

Kuopio Regional Institute of Occupational Health, P.O.B. 95, FIN-70701 Kuopio, Finland

RO Juvonen

Department of Pharmacology and Toxicology, University of Kuopio, P.O.B. 1627, FIN-70211, Kuopio, Finland

H. Komulainen

National Public Health Institute, Division of Environmental Health, P.O.B. 95, FIN-70701 Kuopio, Finland, Department of Pharmacology and Toxicology, University of Kuopio, P.O.B. 1627, FIN-70211, Kuopio, Finland

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 ole fin, 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.

Key Words: 2-ethylhexanoic acid • cytochrome P450 • man • meta bolism • human liver • microsomes

Human & Experimental Toxicology, Vol. 15, No. 5, 435-442 (1996)
DOI: 10.1177/096032719601500512


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