7-keto-chol

Several oxysterol classes present in oxLDL appear to be cytotoxic toward fibroblasts, ECs, and vascular smooth muscle cells, especially 7-hydroperoxycholes-terol (7-OOH-chol), 7P- and 7a-hydroxycholesterol (7-OH-chol), 7-ketocholesterol (7-keto-chol), and cholesterol epoxides (epoxy-chol). 7p-OOH-chol, a precursor of hydroxyl- and keto-oxysterols, was reported to be the most toxic. During LDL oxidation 7P-OOH-chol was produced in three to five times higher quantities than 7a-OOH-chol, other oxysterols and even hydroxy-nonenal, which is one of the most abundant lipid oxidation products. Cytotoxicity of oxysterols was connected to increased cellular oxidative stress. Some studies suggest that oxysterols are even involved in oxidative stress induction. Animal models indicate that dietary oxysterols can significantly decrease glutathione levels and increase expression of glutathione peroxidase and superoxide dismutase. In apolipoprotein-deficient mice, the NADPH-oxidase activity was induced by 7-keto-chol, 7p-OH-chol, and Sp,6P-epoxy-chol. The increased activity of NADPH oxidase yields more superoxide anions that amplify oxidative stress. 

In a recent report Nakada et al. (89) detailed the preparation of 3,7-dioxo-5a-cholanoic acid (m.p. 185-187 °C) from 3 -hydroxy-7-keto-chol-5-enoic acid obtained from oxidation of 3/3-hydroxy-chol-5-enoic acid with CrOg and subsequent reduction. Reduction of this material should provide the 3jS-epimer of allochenodeoxycholic acid and its 7p-epimer. 

Pathways of Synthesis. Sulfated steroids are produced by human adrenals from both P - and 20a-0H-Chol. The failure of chicken adrenals to use Chol 3 is overcome by solubilizing high specific activity material with Tween 80. The failure of 20a-0H,22-keto-Chol to trap the radioactivity from Choi mediates against its being an obligatory intermediate5. 

CHOL is very stable during heating at 100°C for 24 h, but is unstable at temperatures above 120°C (Osada et al., 1993a). When CHOL is heated at 120°C, 7-keto is the predominant OS formed (Osada et al., 1993a). Heating at 150°C results in the production of OS 7-keto > a-epoxide... 

Figure 18.2. Cholesterol autoxidation initiated by peroxy (LOO ) or alkoxyl (LO ) radicals arising from peroxidation of polyunsaturated fatty acids (LH). Compounds are as follows (1) CHOL (2) 7-CHOL (3) CHOO (4) 7a-OOH (5) 7fLOOH (6) CHO (7) 7a-OH (8) 7(3-OH (9) 7-keto (10) 7-keto-3,5-dien. For abbreviations, see Table 18.1.

Figure 18.7. Major pathways of cholesterol oxidation A, CHOL B, 7-OOH (7< -and 7(3-OOH) C, 7-OH (7a-and 7(3-OH) D, 7-keto E, epoxides (a-and (3-epoxides), ki-ks, rate constants of the reactions of cholesterol oxidation. For abbreviations, see Table 18.1.

There is indirect evidence for the reduction of 12a-hydroxy-3-keto-4,6-chol-adienic acid at A. Hayakawa and collaborators (H-358, H-367, T-974) have shown that cholic acid is transformed into the illustrated products (1-5) by Corynebacterium simplex and other Corynebacterium sp. 

The method of Chakravarti, Chakravarti, and Mitra (84) for the transformation,of 3-hydroxy-5 steroids to 3-keto-5a steroids has been utilized by Danielsson et al. (34) for the preparation of methyl 12a-hydroxy-3-keto-5a-cholanoate from the corresponding 5 3 derivative, and by Anderson and Haslewood (69) for the preparation of ethyl 3 3,7 ,r2 -trihydroxy-5a-chol-anoate from ethyl 7a,12a-dihydroxy-3-keto-5a-cholanoate in boiling cymene. The latter authors have commented on the poor and capricious yields obtained by this procedure (25). 

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