Effect of leptin on cytochrome P-450, conjugation, and antioxidant enzymes in the ob/ob mouse.
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.
Watson
A M
AM
College of Pharmacy, Division of Pharmaceutical Sciences, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
Poloyac
S M
SM
Howard
G
G
Blouin
R A
RA
D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D003345:Corticosterone / Q000097:blood; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D005979:Glutathione Peroxidase / Q000378:metabolism; D006900:Hydroxylation; D007328:Insulin / Q000097:blood; D020738:Leptin; D008099:Liver / Q000201:enzymology*; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011506:Proteins / Q000494:pharmacology*; D013739:Testosterone / Q000378:metabolism
D000975:Antioxidants; D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D011506:Proteins; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D005979:Glutathione Peroxidase; D014453:Glucuronosyltransferase; D005978:Glutathione; D003345:Corticosterone