Epoxyeicosatrienoic acids (EETs), the eicosanoid biomediators synthesized from 
arachidonic acid by cytochrome P450 epoxygenases, are inactivated in many 
tissues by conversion to dihydroxyeicosatrienoic acids (DHETs). However, we find 
that human skin fibroblasts convert EETs mostly to chain-shortened epoxy-fatty 
acids and produce only small amounts of DHETs. Comparative studies with 
[5,6,8,9,11,12,14,15-(3)H]11,12-EET ([(3)H]11,12-EET) and [1-(14)C]11,12-EET 
demonstrated that chain-shortened metabolites are formed by removal of carbons 
from the carboxyl end of the EET. These metabolites accumulated primarily in the 
medium, but small amounts also were incorporated into the cell lipids. The most 
abundant 11, 12-EET product was 7,8-epoxyhexadecadienoic acid (7,8-epoxy-16:2), 
and two of the others that were identified are 9, 10-epoxyoctadecadienoic acid 
(9,10-epoxy-18:2) and 5, 6-epoxytetradecaenoic acid (5,6-epoxy-14:1). The main 
epoxy-fatty acid produced from 14,15-EET was 10,11-epoxyhexadecadienoic acid 
(10, 11-epoxy-16:2). [(3)H]8,9-EET was converted to a single metabolite with the 
chromatographic properties of a 16-carbon epoxy-fatty acid, but we were not able 
to identify this compound. Large amounts of the chain-shortened 11,12-EET 
metabolites were produced by long-chain acyl CoA dehydrogenase-deficient 
fibroblasts but not by Zellweger syndrome and acyl CoA oxidase-deficient 
fibroblasts. We conclude that the chain-shortened epoxy-fatty acids are produced 
primarily by peroxisomal beta-oxidation. This may serve as an alternate 
mechanism for EET inactivation and removal from the tissues. However, it is 
possible that the epoxy-fatty acid products may have metabolic or functional 
effects and that the purpose of the beta-oxidation pathway is to generate these 
products.