Department of Biological Chemistry and Molecular Pharmacology and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
J Steroid Biochem Mol Biol. 1992 Dec;43(8):1055-72. doi: 10.1016/0960-0760(92)90333-E.
The hydroxylation of cholesterol, bile acids, and steroid hormones by liver cytochrome P450 (CYP) enzymes proceeds with a high degree of regiospecificity, and contributes to both biosynthetic and catabolic pathways of sterol metabolism. CYP 7-catalyzed cholesterol 7α-hydroxylation, a key control point of bile acid biosynthesis, is regulated at a pretranslational step, probably transcription initiation, by multiple factors, including liver bile acid and cholesterol levels, thyroid hormone status, and diurnal rhythm. Hydrophobic bile acids, such as lithocholic acid, are converted to less cholestatic derivatives by 6β-hydroxylation carried out by CYP 3A P450s, which also catalyze steroid hormone 6β-hydroxylation reactions. Complex, gender-dependent developmental patterns characterize the expression of steroid 5α-reductase and several rat liver steroid hydroxylase CYPs. Multiple pituitary-dependent factors regulate the expression of these enzymes; of greatest importance are the gonadal steroids and the sex-dependent secretory patterns of growth hormone (GH) that they impart. The continuous presence of GH in circulation, a characteristic of adult female rats, positively regulates expression of the female-specific steroid disulfate 15β-hydroxylase CYP 2C12, while expression of the male-specific steroid 16α- and 2α-hydroxylase CYP 2C11 is stimulated by the intermittent pituitary secretion of GH that occurs in adult male rats. Intermittent GH can stimulate CYP 2C11 gene expression even when the hormone presents to the hepatocyte at a non-physiological pulse amplitude, duration, and frequency, provided that an interpulse interval of no GH (obligatory recovery period) is maintained for at least 2.5 h. GH regulates the expression of the CYP 2C11 and CYP 2C12 genes at the level of transcription initiation. This process is probably mediated by sex-dependent and GH-regulated protein-DNA interactions, such as those observed in the 5'-flank of the CYP 2C12 gene. Thyroid hormone is a second major regulator of liver steroid hydroxylase P450 activity. It regulates these enzymes directly, at a pretranslational step, and indirectly, through its stimulation of pituitary GH secretion and by its positive effects on the expression of the flavoenzyme NADPH-P450 reductase, which catalyzes electron transfer that is obligatory for all microsomal steroid hydroxylation reactions.
肝脏细胞色素 P450（CYP）酶将胆固醇、胆汁酸和类固醇激素羟化，具有高度的区域特异性，有助于固醇代谢的生物合成和分解代谢途径。CYP7 催化的胆固醇 7α-羟化是胆汁酸生物合成的关键控制点，受多种因素调节，包括肝内胆汁酸和胆固醇水平、甲状腺激素状态和昼夜节律。疏水性胆汁酸，如胆酸，通过 CYP3A P450 进行的 6β-羟化转化为较少的亲胆性衍生物，CYP3A P450 还催化类固醇激素 6β-羟化反应。类固醇 5α-还原酶和几种大鼠肝类固醇羟化酶 CYP 的表达具有复杂的、性别依赖性的发育模式。多种垂体依赖性因素调节这些酶的表达；最重要的是性腺类固醇和它们赋予的生长激素（GH）的性别依赖性分泌模式。GH 在循环中的持续存在是成年雌性大鼠的特征，正向调节雌性特异性类固醇硫酸盐 15β-羟化酶 CYP2C12 的表达，而雄性特异性类固醇 16α-和 2α-羟化酶 CYP2C11 的表达则受成年雄性大鼠中发生的 GH 间歇性垂体分泌的刺激。间歇性 GH 可以刺激 CYP2C11 基因表达，即使激素以非生理脉冲幅度、持续时间和频率呈现给肝细胞，只要维持至少 2.5 小时的无 GH 脉冲间隔（必需的恢复期）。GH 通过转录起始水平调节 CYP2C11 和 CYP2C12 基因的表达。该过程可能是通过性别依赖性和 GH 调节的蛋白质-DNA 相互作用介导的，如在 CYP2C12 基因 5'-侧翼观察到的相互作用。甲状腺激素是肝脏类固醇羟化酶 P450 活性的另一个主要调节剂。它直接在翻译前步骤调节这些酶，通过刺激垂体 GH 分泌并通过其对黄素酶 NADPH-P450 还原酶表达的积极影响间接调节，该酶催化所有微粒体类固醇羟化反应所必需的电子转移。
