Review Article
Vascular Cytochrome P450 Enzymes: Physiology and Pathophysiology

https://doi.org/10.1016/j.tcm.2007.11.002Get rights and content

Cytochrome P450 epoxygenases and the soluble epoxide hydrolase are enzymes that regulate the cellular content of bioactive epoxides such as the epoxyeicosatrienoic acids derived from arachidonic acid. Epoxyeicosatrienoic acids are recognized as lipid mediators that participate in vascular signaling processes such as the acute regulation of vascular tone and the processes of inflammation and angiogenesis.

Introduction

Cytochrome P450 enzymes are classically linked to detoxification processes in the liver but are also expressed in other cell types, in which they can utilize endogenous substrates to generate intracellular second messengers. This review concentrates on describing the physiological and pathophysiological implications of alterations in the expression and activity of the vascular arachidonic acid epoxygenases.

Section snippets

Cytochrome P450 Enzymes

Cytochrome P450 (CYP) enzymes are membrane-bound, heme-containing terminal oxidases that exist as part of a multienzyme system that includes an flavin adenine dinucleotide/flavin mononucleotide–containing nicotinamide adenine dinucleotide phosphate CYP reductase and cytochrome b5. Although many CYP isozymes can also oxidize numerous endogenous substrates, such as eicosapentaenoic acid, retinoic acid, and linoleic acid, they are often referred to as the third pathway of arachidonic acid

Vasodilatation

Epoxyeicosatrienoic acids are vasodilator eicosanoids, and CYP-derived EETs have been implicated in nitric oxide (NO) and prostacyclin (PGI2)-independent vasodilatation in a number of (but not all) vascular beds, in particular coronary and renal arteries from humans, pigs, cows, dogs, rats, and rabbits (for review, see Michaelis and Fleming 2006). Although it is possible to specifically target CYP enzymes in isolated arteries from experimental animals to demonstrate the importance of

Cytochrome P450 Enzymes and Vascular Disease

Given that the EET/EDHF pathway is assumed to be a backup vasodilator mechanism to ensure vasodilatation in the absence of NO or following a decrease in its bioavailability, it would make sense to look for associations with alterations in the generation and or breakdown of EETs in different cardiovascular diseases.

Cytochrome P450 enzymes and cardiovascular disease are potentially linked at two levels. The first relates to the role of EETs in the regulation of vascular homeostasis (described

What's EETing the Lung?

Admittedly, the literature on this topic was controversial for quite a long time, with EETs being reported to have both vasodilator and vasoconstrictor actions depending on which branch of the pulmonary vascular tree was assessed (Jacobs and Zeldin 2001). However, it now seems that the activation of CYP epoxygenases in the lung potentiates hypoxia-induced pulmonary vasoconstriction and promotes the development of pulmonary hypertension. The molecular mechanisms underlying this effect are

Cytochrome P450 Enzymes and Cancer

Given the evidence linking EETs to angiogenesis, it makes sense to look for similarly strong links to cancer. Several CYP enzymes are expressed at higher levels in cancerous tissue than in noncancerous tissue from the same individuals (Jiang et al. 2005), and high CYP expression/activity has been linked to increased tumor malignancy (Jiang et al. 2007). However, such global statements seem to be dependent on the type of cancer investigated and are generally controversial (Bergheim et al. 2007).

Polymorphisms

Given the anti-inflammatory properties attributed to the EETs, it is tempting to look for a link between gain and loss of function polymorphisms of the CYP epoxygenase and sEH (EPHX2) genes and vascular disease.

Outlook

Because the first proposal that CYP-derived metabolites of arachidonic acid may be linked to vascular smooth muscle hyperpolarization and relaxation, it has become clear that the arachidonic acid epoxides (5,6-, 8,9-, 11,12-, and 14,15-EET) are important intracellular signaling molecules that modulate much more than membrane potential. The vasodilator and anti-inflammatory actions of EETs mean that therapies that increase their generation or prevent their degradation may prove beneficial in the

Acknowledgments

The author acknowledges the work of the many groups whose work has not been possible to cite here because of space limitations. Work performed in the authors' own laboratory was supported by the Deutsche Forschungsgemeinschaft (SFB-TR 23, A6 and GRK 757).

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