The arachidonic acid monooxygenase: from biochemical curiosity to physiological/pathophysiological significance

Abstract

The initial studies of the metabolism of arachidonic acid (AA) by the cytochrome P450 (P450) hemeproteins sought to: a) elucidate the roles for these enzymes in the metabolism of endogenous pools of the FA, b) identify the P450 isoforms involved in AA epoxidation and ω/ω-1 hydroxylation, and c) explore the biological activities of their metabolites. These early investigations provided a foundation for subsequent efforts to establish the physiological relevance of the AA monooxygenase and its contributions to the pathophysiology of, for example, cancer, diabetes, hypertension, inflammation, nociception, and vascular disease. This retrospective analyzes the history of some of these efforts, with emphasis on genetic studies that identified roles for the murine Cyp4a and Cyp2c genes in renal and vascular physiology and the pathophysiology of hypertension and cancer. Wide-ranging investigations by laboratories worldwide, including the authors, have established a better appreciation of the enzymology, genetics, and physiologic roles for what is now known as the third branch of the AA cascade. Combined with the development of analytical and pharmacological tools, including robust synthetic agonists and antagonists of the major metabolites, we stand at the threshold of novel therapeutic approaches for the treatment of renal injury, pain, hypertension, and heart disease.

Keywords: PPAR; diseases; eicosanoids; endothelial cells; genetics; kidney.

Fig. 1.

The AA monooxygenase.

Fig. 2.

The Cyp4a14 gene and the pathophysiology of sexually dimorphic hypertension (56). Arrows pointing up denote increases in expression or functional responses. The dashed arrow indicates that the Cyp4a14 gene regulates plasma androgens by unknown mechanism(s).

Fig. 3.

The Cyp4a10 gene and the pathophysiology of SS hypertension (57). Arrows pointing up or down denote increases or reductions in expression or functional responses, respectively. The dashed arrow indicates that the Cyp4a10 gene regulates the SS expression of renal Cyp2c44 by unknown mechanisms.

Fig. 4.

The renal Cyp2c44 is a dietary SS pronatriuretic and antihypertensive epoxygenase (58). Arrows pointing up or down denote increases or reductions in expression or functional responses, respectively.

Fig. 5.

The Cyp2c44 gene and dietary NaCI- and/or KCI-sensitive hypertension on mice carrying a Cyp2c44 gene disrupted globally (58) (A), or in the CD segment of the ASDN (59) (B). Arrows pointing up or down denote increases or reductions in expression or functional responses.

Fig. 6.

Schematic, nonscale, representations of an ASDN principal cell showing in its apical membrane: ENaC (hatched circle), ROMK (hatched oval), BK_ca (empty oval), and NCC (gray square), and basolateral membrane: NafK ATPase and inward rectifying Kir 4.1/4.5 K⁺ channels (A); the zonal distribution of principal cells expressing ENaC and NCC along a segment of the ASDN (B); and the effects of HS- or HK-containing diets in the zonal upregulation of the Cyp2c44 epoxygenase and the biosynthesis of ENaC inhibitory EETs (C) (59).

Fig. 7.

By its effects on NCC activity, dietary K⁺ regulates the partition between electroneutral (NCC-driven) and electrogenic Na⁺ (ENaC-driven) Na⁺ excretion. Arrows pointing up or down denote increases or reductions in expression or function.

Fig. 8.

Wy ameliorates human NSCLC primary and metastatic growth. GFP-A459 cells were injected into the left lungs of athymic mice, and animals were then separated into an untreated group (a) or groups treated with Wy immediately after injection (groups b and c) or 2 weeks after (group d). For group c, Wy treatment was stopped 2 weeks after initiation. All mice were euthanized 5 weeks after the cell injections, and the number of primary (left lung) and metastatic (right lung and liver) tumors were determined in the dissected organs by the number of surface GFP-positive structures/microscopic field. n = 6 mice/group (42).

Fig. 9.

Monooxygenase-inspired drugs in clinical trials.