Watson A M, Poloyac S M, Howard G, Blouin R A
College of Pharmacy, Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
Drug Metab Dispos. 1999 Jun;27(6):695-700.
Leptin is a hormone that is secreted by adipocytes and regulates body weight through its effect on satiety and energy metabolism. The ob/ob mouse is deficient in this protein and is characterized by obesity and other metabolic disorders. This study investigated the alterations of several hepatic cytochrome P-450 (CYP), conjugation, and antioxidant enzymes in lean and ob/ob mice and the role leptin plays in the modulation of these enzymes. Lean and ob/ob male mice were injected with leptin (100 microg) or PBS for 15 days. Liver microsomes from ob/ob mice, when compared with lean controls, displayed significantly reduced chlorzoxazone 6-hydroxylation activity (27%); however, 7alpha- and 16alpha- testosterone hydroxylation and pentoxyresorufin O-dealkylation activities were significantly higher (47%, 22%, and 39%, respectively). Leptin administration corrected alterations seen with all P-450 activities. Dealkylation of ethoxyresorufin and omega-hydroxylation of lauric acid activities from ob/ob and lean mice were not statistically different; however, leptin exposure significantly increased ethoxyresorufin activity in lean mice (14%) and decreased the activity in ob/ob mice (36%). UDP-glucuronosyl-transferase and glutathione S-transferase activities were not altered. The antioxidant enzymes, catalase (11%) and glutathione peroxidase (26%), as well as glutathione reductase (17%), were lower in the ob/ob mice and leptin treatment corrected these alterations. The results of this study demonstrate alterations in constitutive expression of CYP2B, CYP2E, CYP2A, catalase, glutathione peroxidase, and glutathione reductase in ob/ob mice that were restored to lean control values following leptin treatment. Additionally, CYP3A activity was increased following leptin treatment in ob/ob mice. The mechanism for the observed alterations may be due to direct leptin effects or via indirect alterations in insulin, corticosterone, and/or growth hormone.
瘦素是一种由脂肪细胞分泌的激素，它通过对饱腹感和能量代谢的影响来调节体重。ob/ob小鼠缺乏这种蛋白质，其特征是肥胖和其他代谢紊乱。本研究调查了瘦小鼠和ob/ob小鼠中几种肝脏细胞色素P-450（CYP）、结合酶和抗氧化酶的变化，以及瘦素在这些酶调节中的作用。将瘦小鼠和ob/ob雄性小鼠注射瘦素（100微克）或磷酸盐缓冲盐水（PBS），持续15天。与瘦素对照组相比，ob/ob小鼠的肝脏微粒体显示氯唑沙宗6-羟化活性显著降低（27%）；然而，7α-和16α-睾酮羟化以及戊氧基试卤灵O-脱烷基化活性显著更高（分别为47%、22%和39%）。给予瘦素可纠正所有P-450活性的变化。ob/ob小鼠和瘦小鼠的乙氧基试卤灵脱烷基化和月桂酸ω-羟化活性在统计学上没有差异；然而，瘦素处理显著增加了瘦小鼠的乙氧基试卤灵活性（14%），并降低了ob/ob小鼠的活性（36%）。尿苷二磷酸葡萄糖醛酸基转移酶和谷胱甘肽S-转移酶活性没有改变。抗氧化酶，过氧化氢酶（11%）、谷胱甘肽过氧化物酶（26%）以及谷胱甘肽还原酶（17%）在ob/ob小鼠中较低，瘦素处理纠正了这些变化。本研究结果表明，ob/ob小鼠中CYP2B、CYP2E、CYP2A、过氧化氢酶、谷胱甘肽过氧化物酶和谷胱甘肽还原酶的组成型表达发生了变化，瘦素处理后恢复到瘦素对照组水平。此外，ob/ob小鼠在瘦素处理后CYP3A活性增加。观察到的变化机制可能是由于瘦素的直接作用或通过胰岛素、皮质酮和/或生长激素的间接变化。
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