Cholesterol, Reactive Oxygen Species, and the Formation of Biologically Active Mediators

A Peroxygenase from Chaetomium globosum Catalyzes the Selective Oxygenation of Testosterone

“…Compound 1 a , a steroid containing a 4,5‐epoxy‐3‐oxo moiety, is of special relevance for synthetic applications and biological activities, as epoxy steroids are involved in the regulation of cell proliferation and cholesterol homeostasis 40. The synthetic versatility of epoxides has established them as useful precursors to obtain a variety of polyfunctional derivatives or rearranged compounds 41, 42, 43, 44, 45, 46, 47.…”

Conversion of 7-Dehydrocholesterol to 7-Ketocholesterol Is Catalyzed by Human Cytochrome P450 7A1 and Occurs by Direct Oxidation without an Epoxide Intermediate

“…Cholesterol has been the presumed precursor of 7-ketocholesterol, but the mechanism of formation of 7-ketocholesterol in the body is unclear. Much of the literature attributes its source to lipid peroxidation and other radical processes acting on cholesterol (16,28,(32)(33)(34)(35). A 7-hydroxycholesterol dehydrogenase was purified from hamster liver microsomes, although the enzyme is apparently not present in rats or (most) humans (36).…”

99. Cholesterol oxidation products are sensitive and specific blood-based biomarkers for Niemann–Pick C1 disease

“…These oxysterols, which include 24-, 25-and 27-HC, are predominantly synthesized by cytochrome P450 enzymes that reside in the ER (e.g., CYP46A1) and mitochondria (e.g., CYP27A1). In contrast to side-chain oxysterols, steroid ring-modified oxysterols are principally generated non-enzymatically as a result of the susceptibility of the C-5,6 double bond and the C-7 vinylic methylene group of cholesterol to radical and nonradical oxidation reactions (29,30). The major products of freeradical based oxidation of cholesterol include 7α-HC, 7β-HC, 7-KC and the epimeric 5,6-epoxides (30).…”

“…In vivo, multiple mechanisms are likely responsible for generation of the free radicals responsible for cholesterol oxidation, including iron-catalyzed reduction of H 2 O 2 by superoxide by iron or peroxynitrite (30). Superoxide anions interact with polyunsaturated fatty acyl chains in membranes to produce hydroperoxy lipid radicals that are required for formation of both 5,6-epoxycholesterols, the precursor to 3β,5α,6β-triol, and 7-KC.…”

“…In contrast to side-chain oxysterols, steroid ring-modified oxysterols are principally generated non-enzymatically as a result of the susceptibility of the C-5,6 double bond and the C-7 vinylic methylene group of cholesterol to radical and nonradical oxidation reactions (29,30). The major products of freeradical based oxidation of cholesterol include 7α-HC, 7β-HC, 7-KC and the epimeric 5,6-epoxides (30). The latter species are abundant in oxidized LDL and in macrophages, and serve as substrates for the ubiquitous cholesterol epoxide hydrolase to yield 3β,5α,6β-triol (29,31).…”