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Abstract
Epoxyeicosatrienoic acids (EETs) generated from arachidonic acid by cytochrome P450 (CYP) epoxygenases have beneficial effects in certain cardiovascular and kidney diseases. Hence, great efforts have been made to develop drugs targeting the EET pathway. Some of these agents are currently under evaluation in clinical trials for treatment of hypertension and diabetes. In this issue of the JCI, Panigrahy et al. evaluate in a systematic way the role of CYP epoxygenases and the metabolites they generate in cancer progression. Their findings, along with previous studies, raise concerns about using these drugs in humans.
Authors
Dingzhi Wang, Raymond N. DuBois
Figure 1
An overview of CYP epoxygenase pathways and how they can be modulated.
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AA is a polyunsaturated fatty acid that constitutes the phospholipid domain of most cell membranes. It is liberated from cellular membranes by cPLA2. Free AA can be metabolized through three major pathways: the PTGS/COX pathway, the LOX pathway, and the CYP pathway. In the CYP pathway, AA is converted to EETs and HETEs by CYP epoxygenases and CYP ω-hydroxylases, respectively. The EETs are then further metabolized to less active DHETs by sEH. MSPPOH is a selective inhibitor of CYP epoxygenases, and HET0016 is a selective inhibitor of CYP ω-hydroxylases. AR9281 is a selective inhibitor of sEH and is currently under evaluation in phase II clinical trials as a treatment for patients with hypertension and type 2 diabetes.
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ISSN: 0021-9738 (print), 1558-8238 (online)