Following his 1981 report on the involvement of microsomal cytochrome P450 (P450) enzymes in arachidonic acid (AA) oxidation, [6] Capdevila conducted foundational studies on the biochemical and enzymatic properties of this metabolic pathway. [5] These investigations led to two key advances:
- Structural identification of the 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids (EETs) [7] and 19- and 20-hydroxyeicosatetraenoic acids (19- and 20-HETE) [8] as products of the epoxygenase and ω-hydroxylase branches of the P450 AA monooxygenase, respectively. [5] [9] [10]
- Characterization of EETs as endogenous metabolites of AA in rodent and human organs, [11] establishing the AA epoxygenase pathway as a physiologically relevant system. [9] [10] [11]
Subsequent work by Capdevila's laboratory identified:
- Roles for CYP2 subfamily enzymes in endogenous EET biosynthesis; [11]
- Novel endogenous glycerolipid pools containing esterified EET moieties; [12]
- Soluble epoxide hydrolase (sEH; Epoxide hydrolase 2) as the enzyme responsible for catalyzing EET hydration to vicinal dihydroxyeicosatrienoic acids (DHETs), a step preceding their urinary excretion. [9] [13]
Current research focuses on developing soluble epoxide hydrolase inhibitors to modulate organ-specific EET levels and their biological effects. [14]
Physiological and Pathophysiological Roles of the Arachidonic Acid Monooxygenase Pathway
Capdevila's research group provided unequivocal genetic and biochemical evidence that, as suggested earlier, [24] members of the P450 murine Cyp4a and Cyp2c gene subfamilies participated in the control of systemic blood pressures [25] by showing that targeted disruption of the: a) Cyp4a14 gene caused a type of hypertension that was male-specific and associated with increases in plasma androgens, the renal expression of the Cyp4a12 AA omega hydroxylase, and the biosynthesis of pro-hypertensive 20-HETE. [19] [26] The potential clinical relevance of these studies was highlighted by reports of associations between a functional variant of the human CYP4A11 20-HETE synthase (the T8590C polymorphism) [27] and hypertension in White Americans, [27] [28] hypertension, the progression of kidney disease in African-Americans, [29] and risk of hypertension in German and Japanese cohorts; [30] b) Cyp4a10 gene downregulated the expression of the kidney Cyp2c44 epoxygenase, leading to reductions in renal EET biosynthesis and the development of dietary salt sensitive hypertension; [31] and c) Cyp2c44 gene caused dietary salt-sensitive hypertension linked to reductions in renal EET biosynthesis and excretion, as well as increases in sodium retention in the distal nephron. [32] Abnormalities in the regulation of urinary EET pools in normotensive, dietary salt-sensitive, individuals have been reported. [33] Collectively, these studies identified: a) 20-HETE as a renal vasoconstrictor and pro-hypertensive lipid; [19] [22] [23] [25] and b) 11,12-EET as an endogenous natriuretic and anti-hypertensive mediator. [5] [17] [25] [32] Additionally, they demonstrated that salt-sensitive hypertension could result from either a down regulation or lack of a functional Cyp2c44 epoxygenase. [5] [25] [31] These achievements, highlighted in independent reviews, [19] [20] [21] [22] [23] contributed as an stimulant to ongoing efforts to further define the physiological and pathophysiological relevance of the AA Monooxygenase enzymes and its metabolites, as well as potentially novel targets for drug development.
More recently, Capdevila participated in: a) the identification of roles for the Cyp2c44 epoxygenases and the EETs in tumor vascularization [34] and progression in rodent models of human non-small-cell-lung cancer (NSCLC); [35] and b) in clinical studies showing improved survival in female cases of NSCLC that were carriers of two known reduction of function variants of the human CYP2C9 epoxygenase gene. [36]
In summary, Capdevila and collaborators contributed to the initial discovery and characterization of roles for the CYP450 monooxygenases in the metabolism and bio-activation of endogenous arachidonic acid, the identification of its role in the in vivo regulation of cell, organ, and body physiology, and to its present status as a physiological/pathophysiological important metabolic pathway. [5]
