Fatty Acid and Leukotriene Monooxygenases

Several mechanism-based irreversible inhibitors of P450-dependent arachidonic acid metabolism have also been developed. For instance, in 

11-dodecynoic acid, the terminal acetylenic analog of lauric acid, and 10-undecynoic acid have been shown to inactivate hepatic CYP4A lauric acid ( )-hydroxylases while minimally altering the spectrophotometrically detectable hepatic P450 content or function . 

CYP4A inactivator Administration of a single dose of 10-SUYS, a potent and selective mechanism-based CYP4A inactivator, acutely reduced the mean arterial blood pressure as well as the urinary 20-HETE excretion in spontaneously hypertensive rats, consistent with the inactivation of renal 20-HETE formation . These findings thus suggest that 20-HETE could play an important role in blood pressure regulation in hypertensive states and that the inhibition of its synthesis in these conditions may be of therapeutic benefit . 

The acetylenic fatty acids 15-hexadec5moic (15-HDYA) and 17-ODYA have also been explored as modulators of leukotriene (LTB ), an important and clinically relevant inflammatory mediator, and its physiologically active (o-hydroxylated metabolite . Both 15-HDYA and 17-ODYA inactivated the polymorphonuclear leukocytic LTB o-hydroxylase in whole cells and cell lysates . In contrast, the shorter-chain acid, 10-undecynoic acid was much less effective, while the saturated analogs of 15-HDYA and 17-ODYA were inactive. 15-HDYA and 17-ODYA also inactivate pulmonary prostaglandin (o-hydroxylases . 

The mechanism-based inactivator 1-ABT (Section 3.3.5), which is not very selective and inactivates multiple P450 enzymes, including those responsible for the S3mthesis of both EETs and 20-HETE, has also been used, alone or in conjunction with other inhibitors, to assess the role of these metabolites in skeletal muscle angiogenesis induced by electrical stimulation as well as in the renal and vasoconstrictor actions of angiotensin .  

---