ROLE OF CYTOCHROME-P-450 ENZYMES AND METABOLITES OF ARACHIDONIC-ACID IN THE CONTROL OF VASCULAR TONE

The metabolism of arachidonic acid (AA) into vasoactive products by cy clo-oxygenase and lipoxygenase enzymes has been well described, as has their biological relevance. Recently, a number of studies have demons trated the ability of cytochrome P-450 (P450) enzymes to metabolize AA into biologically important regulators of vascular tone. There are tw o categories of vasoactive P450 metabolites, namely those catalyzed by epoxygenase enzymes which generate epoxyeicosatrienoic acids (EETs) a nd those enzymes which generate hydroxyeicosatetraenoic acids (HETEs). Except for 20-HETE, P450 metabolites of AA occur as stereo- and regio isomers which determine, to some extent, their biological activity. 5, 6-, 8,9-, 11,12- and 14, 15-EETs are generally potent dilators in a nu mber of vascular beds with a sensitivity which appears to increase as the vasculature decreases in size toward capillaries. HETEs, such as 1 2R- and 20-HETE, can be potent activators of vascular tissue with 20-H ETE contracting cerebral and renal microvessels at concentrations of < 10-(10) M. Both EETs and HETEs can be made by vascular and extravascul ar tissue. Available data suggests that EETs are formed by endothelial and parenchymal tissue while HETEs can be endogenously formed in arte rial muscle where they appear to act as second messengers. This review will discuss the molecular biology, stereochemistry, biological activ ity and importance of P450 metabolites of AA as para- and autocrine co ntrollers of organ blood flow. We will also discuss the large diversit y of P450 enzyme isoforms and how such diversity can provide for preci se physiological control of vascular tone.