FIG. 7.

Arachidonic acid-ceramide-apoptosis-signaling pathway is regulated by cytochrome P450 in LLCPKcl4 cells. Arachidonic acid, an important constituent of cell membrane, is released by activation of specific phospholipases (PLA₂) and further metabolized by cyclooxygenases, lipoxygenases, and cytochrome P450 pathways. If unesterified arachidonic acid is not metabolized, it activates neutral sphingomyelinase (N-SMase), which converts sphingomyelin to the second messenger, ceramide. Ceramide induces caspase activation, which leads to apoptosis. In cells such as the renal proximal tubule, in which cyclooxygenase and lipoxygenase are expressed at nearly undetectable levels, arachidonic acid metabolism is shunted to the cytochrome P450 pathway. This metabolism not only metabolizes and detoxifies excess unesterified arachidonic acid to prevent proapoptotic ceramide formation but also produces a metabolite, 14,15-EET, which activates a PI-3 kinase–Akt-signaling pathway. Thus, cytochrome P450 mediates cell survival by two complementary mechanisms.