Submitted on April 6, 2009
Revised on May 29, 2009
Accepted on June 15, 2009
Detection of EETs and HETEs-generating Cytochrome P450 Enzymes and the Effects of their Metabolites on Myometrial and Vascular Function
Timothy Pearson1, Averil Y Warren1, David A Barrett1, and Raheela N Khan1*
1 University of Nottingham
* To whom correspondence should be addressed. E-mail: raheela.khan{at}nottingham.ac.uk.
Cytochrome P450 (CYP 450) enzymes of the 2 and 4 family in humans metabolise arachidonic acid to generate bioactive epoxyeicosatrienenoic acids (EETs) and hydroxyeicosatetrenoic acids (HETEs). We report significantly higher levels of CYP 2J2 protein expression following the onset of labor (n = 6; P < 0.05) implying increased EET-generating capacity within the uterus. Myometrial relaxation to 8,9 EET and 5,6 EET was observed with the latter being inhibited by preincubation with 1 M paxilline and is supported by whole cell recordings showing a modest effect of 5,6-EET on myometrial outward current density (n = 4; P < 0.05). Only 5,6 EET of the EETs tested affected vascular reactivity (n = 6). Both 12- and 20-HETE (n = 5-6) caused vasoconstriction of partially depolarised blood vessels with glibenclamide (n = 5) enhancing the effect of 12-HETE alone. Our findings signify a role for CYP 2C9/19, 2J2 and 4A11/22 in late pregnancy, possibly related to the synthesis of lipid metabolites and downstream effects on vascular remodeling in the term pregnant uterus. The presence of CYP4A11/22 and their resultant pro-contractile metabolites could argue either a role in the control and initiation of labor and/or modification of the vascular delivery system to influence blood flow to the labouring uterus. The differential effects of the EETs and HETEs in the pregnant human uterus identify the CYP pathway as a novel modulator of myometrial and vascular physiology during late pregnancy.
