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.
Highlights
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 / -1 hydroxylation, and c) explore the biological activities of their metabolites
Thanks to the recognition of the novelty and potential importance of these studies by the staff and reviewers at the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of General Medical Sciences, critical financial support was provided to our laboratories to initiate the chemical, biochemical, and functional characterizations of the AA monooxygenase pathway
We provide a more or less temporal sequence of events and a personal view of the crucial observations and concepts, especially in renal and vascular physiology/pathophysiology, that helped bring this area of study to its present status as the third branch of the AA cascade
Summary
Our exploration of roles for the cytochrome P450 (P450) enzyme system in arachidonic acid (AA) metabolism and bioactivation became part of an exciting, challenging, and rewarding journey that allowed us to pursue goals that at times seemed unrealistic and/or nearly impossible, but with the help and example of many collaborators contributed to our growth as scientists and individuals. One can only speculate if that would be the case today As we initiated these studies, priority was placed upon substantiating whether: a) the AA monooxygenase participated in the metabolism of endogenous pools of AA, i.e., it is a formal metabolic pathway; b) its metabolites were biologically active; and c) the enzymes and products of the AA monooxygenase were physiologically and/or pathophysiologically relevant. With evidence of biological significance, we would proceed to the identification of functionally relevant P450 isoforms, the characterization of their enzymatic properties, organ/tissue expression and regulation, roles in animal models of genetically determined organ dysfunction, and, their physiological/pathophysiological relevance and potential biomedical significance Overall progress in this field of studies has followed more or less the above sequence, with work many different laboratories worldwide contributing to the identification of new functionalities for AA monooxygenase ranging from, for example, hypertension, vascular diseases, cancer, diabetes, inflammation, to nociception. Rat CYP2C23 and mouse Cyp2c44, the predominant AA epoxygenases in the rat and mouse kidney and endothelium (11, 35–37), are unique in that: a) they
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