Cholesterol Autoxidation Revisited: Debunking the Dogma Associated with the Most Vilified of Lipids.

The longstanding dogma that cholesterol (chol) autoxidation gives chol 7-hydroperoxide (7-OOH) as the sole primary product is shown to be invalid. In fact, the epimers of each of chol 4-OOH, 6-OOH, and 7-OOH are readily formed. Although the C4-H bond that must be cleaved to produce the chol 4-OOH and 6-OOH products is significantly stronger than the C7-H bond, H-atom abstraction from C4 is facilitated by H-bond formation between the attacking peroxyl radical and the 3β-OH. Chol 5α-OOH is also formed, but only in the presence of a good H-atom donor. Chol 5α-OOH and 6-OOH undergo Hock fragmentation to yield the secosterols implicated in cardiovascular and neurodegenerative diseases, suggesting that they are likely to arise simply from autoxidation and not from reactions with O3 or (1)O2.