Abstract
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 μg) 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, 7α- and 16α- testosterone hydroxylation and pentoxyresorufinO-dealkylation activities were significantly higher (47%, 22%, and 39%, respectively). Leptin administration corrected alterations seen with all P-450 activities. Dealkylation of ethoxyresorufin and ω-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 glutathioneS-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.
Footnotes
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Send reprint requests to: Dr. Robert A. Blouin, College of Pharmacy, 907 Rose St., University of Kentucky, Lexington, KY 40536-0082. E-mail: rblou1{at}pop.uky.edu
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This research was supported in part by the Kentucky Spinal Cord and Head Injury Research Trust Grant BB9502 and also in part by National Institute of Diabetes and Digestive and Kidney Diseases Grant 9785. A. W. was supported by the Lyman T. Johnson Postdoctoral Fellowship. S. M. P. was supported by The American Foundation for Pharmaceutical Education.
- Abbreviations used are::
- STAT
- signal transducers and activators of transcription
- CYP
- cytochrome P-450
- GSHPx
- glutathione peroxidase
- GSHRed
- glutathione reductase
- GST
- glutathioneS-transferase
- GH
- growth hormone
- PPAR
- peroxisome proliferator activated receptor
- Received October 30, 1998.
- Accepted March 12, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
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