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, m ouse and human liver microsomes in vitro. The metabolites of 2-EHA wer e identified as methylated derivatives by gas chromatography-mass spec trometry. 2 2-Ethyl-1,6-hexanedioic acid was the main metabolite produ ced in rat, mouse and human liver microsomes. Unsaturated 2-ethyl-5-he xenoic acid, a terminal olefin, was produced only in human liver micro somes and phenobarbital-induced rat liver microsomes. The cytochrome P 450 (CYP) inhibitors metyrapone, SKF 525A, triacetyloleandomycin (TAO) , quinidine and the cytochrome P450 reductase antibody abolished its f ormation both in rat and human microsomes. 3 The metabolites were anal yzed also in vivo in urine of 2-EHA-exposed rats and in urine of sawmi ll workers urine contained 2-ethyl-1,6-hexanedioic acid as the main me tabolite and also 2-ethyl-5-hexenoic acid. Metyrapone, SKF 525A and TA O all decreased drastically the formation of 2-ethyl-5-hexenoic acid i n the rat. 4 The data indicate that (1) several CYP families (CYP2A, C YP2B, 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.