Zhang J, Xue Y, Jondal M, Sjövall J
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
Eur J Biochem. 1997 Jul 1;247(1):129-35. doi: 10.1111/j.1432-1033.1997.00129.x.
Oxygenated derivatives of sterols (oxysterols), including 25-hydroxycholesterol and 27-hydroxycholesterol, have immunosuppressive effects. Oxysterols can directly induce apoptosis in immature thymocytes, cells which are inherently sensitive to induction of programmed cell death. For that reason, the metabolism of 25-hydroxycholesterol and 27-hydroxycholesterol in mouse thymus has been studied. When incubated with thymic tissue, both oxysterols were found to be 7alpha-hydroxylated with subsequent oxidation to 7alpha-hydroxy-3-oxo-delta4 steroids. A minor fraction of 27-hydroxycholesterol was also metabolised to 3beta-hydroxy-5-cholestenoic, 3beta,7alpha-dihydroxy-5-cholestenoic and 7alpha-hydroxy-3-oxo-4-cholestenoic acids. The 7alpha-hydroxylase was found to be localised to the thymic epithelial cells and the reaction was stimulated by interleukin-1beta and inhibited by metyrapone and RU486. In contrast to 25-hydroxycholesterol and 27-hydroxycholesterol, the 7alpha-hydroxylated metabolites, 7alpha,25-dihydroxycholesterol, 7alpha,25-dihydroxy-4-cholesten-3-one and 7alpha,27-dihydroxy-4-cholesten-3-one did not induce thymocyte apoptosis. The results suggest that 7alpha-hydroxylation may be of regulatory importance, possibly by protecting the developing thymocytes against toxic effects by oxysterols.
包括25-羟基胆固醇和27-羟基胆固醇在内的甾醇氧化衍生物具有免疫抑制作用。氧化甾醇可直接诱导未成熟胸腺细胞凋亡，这些细胞对程序性细胞死亡的诱导具有内在敏感性。因此，人们研究了小鼠胸腺中25-羟基胆固醇和27-羟基胆固醇的代谢情况。当与胸腺组织一起孵育时，发现这两种氧化甾醇都发生了7α-羟基化，随后氧化为7α-羟基-3-氧代-δ4类固醇。一小部分27-羟基胆固醇也代谢为3β-羟基-5-胆甾烯酸、3β,7α-二羟基-5-胆甾烯酸和7α-羟基-3-氧代-4-胆甾烯酸。发现7α-羟化酶定位于胸腺上皮细胞，该反应受到白细胞介素-1β的刺激，并被美替拉酮和RU486抑制。与25-羟基胆固醇和27-羟基胆固醇不同，7α-羟基化代谢产物7α,25-二羟基胆固醇、7α,25-二羟基-4-胆甾烯-3-酮和7α,27-二羟基-4-胆甾烯-3-酮不会诱导胸腺细胞凋亡。结果表明，7α-羟基化可能具有调节重要性，可能是通过保护发育中的胸腺细胞免受氧化甾醇的毒性作用。
