Detection of EETs and HETE-generating cytochromeP-450 enzymes and the effects of their metabolites on myometrial and vascular function

Abstract

Cytochrome P-450 (CYP450) enzymes of the CYP2 and -4 family in humans metabolize 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 μM 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 depolarized blood vessels, with glibenclamide ( n = 5) enhancing the effect of 12-HETE alone. Our findings signify a role for CYP2C9/19, -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 procontractile 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 laboring 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.