Epoxide hydrolase in human and rat peroxisomes: implication for disorders of peroxisomal biogenesis

To understand the basis of excretion of excessive amounts of epoxydicarboxylic fatty acids (EDFA) in urine of patients with disorders of peroxisomal biogenesis (Pitt, J. J., and A. Poulos. 1993. Clin. Chim. Acta. 223: 23-29), the activity of epoxide hydrolase (EH) was measured in cultured skin fibroblasts from control subjects and patients with peroxisomal disorders. EH activity was approximately 40% lower in fibroblasts that lack intact peroxisomes (Zellweger syndrome), whereas the activity in other peroxisomal disorders (X-adrenoleukodystrophy and rhizomelic chondrodysplasia punctata) with intact peroxisomes was similar to control. To identify the specific enzyme/organelle that represents the decrease in EH activity in Zellweger cells, we have analyzed this activity in different subcellular organelles from control and Zellweger skin fibroblasts. EH activity was enriched in peroxisomes from control fibroblast. EH activity in isolated mitochondria, microsomes, or cytosol from Zellweger fibroblast was similar to that of control fibroblast. These observations indicate that deficient activity of EH in cells from Zellweger patients is due to lack of peroxisomal EH activity. The peroxisomal EH is differentially induced to a higher degree by ciprofibrate, a hypolipidemic agent and peroxisome proliferator, than EH activity in other organelles and cytoplasm. The high specific activity of EH in peroxisomes and differential induction of EH activity in peroxisomes as compared to other organelles, and the excretion of EDFA in patients who lack peroxisomes suggests that peroxisomal EH may be responsible for the detoxification of EDFA, and that this enzyme in peroxisomes may be a different protein than the EH found in other organelles.