Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P30536 (PBS)
 9,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
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PMID:Effect of leptin on cytochrome P-450, conjugation, and antioxidant enzymes in the ob/ob mouse. 1034 99

The present study was done to determine the effect of trolox C, a hydrophilic analogue of vitamin E, on hepatic injury, especially the alteration in cytochrome P-450 (CYP)-dependent drug metabolism during ischemia and reperfusion (I/R). Rats were subjected to 60 min of hepatic ischemia and 5 h of reperfusion. Rats were treated intravenously with trolox C (2.5 mg/kg) or vehide (PBS, pH 7.4), 5 min before reperfusion. Serum alanine aminotransferase and lipid peroxidation levels were markedly increased after I/R. This increase was significantly suppressed by trolox C. Cytochrome P-450 content was decreased after I/R but was restored by trolox C. There were no significant differences in ethoxyresorufin O-dealkylase (CYP 1A1) and methoxyresorufin O-dealkylase (CYP 1A2) activities among any of the experimental groups. Pentoxyresorufin O-dealkylase (CYP 2B1) activity was decreased and aniline p-hydroxylase (CYP 2E1) activity was increased after I/R. Both these changes were prevented by trolox C. Our findings suggest that trolox C reduces hepatocellular damage as indicated by abnormalities in microsomal drug-metabolizing function during I/R, and that this protection is, in part, caused by decreased lipid peroxidation.
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PMID:Trolox C ameliorates hepatic drug metabolizing dysfunction after ischemia/reperfusion. 1251 Aug 51

All-trans-retinoic acid (ATRA) is now included in many antitumor therapeutic schemes for the treatment of acute promyelocytic leukaemia, Kaposi's sarcoma, head and neck squamous cell carcinoma, ovarian carcinoma, bladder cancer and neuroblastoma. Unfortunately its poor aqueous solubility hampers its parenteral formulation. To date, there is no parenteral formulation of ATRA commercially available and oral administration of ATRA is associated with progressively diminishing ATRA levels in plasma, which is related to induction of retinoic acid-binding protein and increased drug catabolism by cytochrome P-450-mediated reaction. An ATRA formulation, obtained by complexation of the drug into polymeric micelles, might be suitable for parenteral administration overcoming these unwanted effects. To this purpose we prepared an amphiphilic polymer by polyvinylalcohol (PVA) substitution with oleyl amine at 1.5% substitution degree (mol substituent per 100 mol hydroxyvinylmonomer) and evaluated its functional properties with regard to ATRA complexation. The substituted polymer displayed ability to interact with ATRA both in aqueous solution and in the solid state following spray-drying of drug-polymer hydro-alcoholic solutions. The spray-dried complexes rapidly dissolved in water providing high levels of ATRA solubilization as a function of the drug-polymer weight ratio. The complexes characterized by 1:5 drug-polymer weight ratio provided higher levels of ATRA solubilization than 1:3 and 1:10 drug-polymer weight ratios respectively. Pre-formed polymeric micelles in water equilibrated in the presence of excess solid ATRA provided the lowest levels of solubilization. The drug release from the complexes was very slow in PBS, indicating their suitability in antitumor drug targeting where a fundamental requirement is stability towards drug release for at least 24 h, corresponding to the average circulation time period of macromolecular carriers. The cytotoxicity studies against neuroblastoma cell lines outlined increased cytotoxicity of complexed ATRA with respect to free ATRA, likely due to the increased bioavailability of the hydrophobic drug from the complex. We conclude that ATRA entrapped into self-assembling polymer micelles may be a useful parenteral ATRA formulation overcoming the unwanted pharmacological mechanism that lead to acquired retinoid resistance.
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PMID:Modified polyvinylalcohol for encapsulation of all-trans-retinoic acid in polymeric micelles. 1576 20

Amnesic shellfish poisoning toxin domoic acid (DA) is a marine neurotoxin that accumulates in fish and shellfish, and has been implicated to be involved in human and marine wildlife mortality. The transcriptional responses of cytochrome P-450 1A (CYP1A), glutathione S-transferase alpha (GSTA), glutathione S-transferase rho (GSTR), heat shock protein 70 (HSP70), and Na(+)/K(+)-ATPase alpha 1 (ATP1A1) in the liver of rabbitfish (Siganus oramin) intracoelomically injected with DA, were investigated. Experimental fish were administered with one injection of DA (2 microg/g wet weight) or PBS as control. After 24 h, fish were killed and hepatic RNA was isolated. Partial cDNA of rabbitfish CYP1A, GSTA, GSTR, HSP70, ATP1A1, and beta-actin were obtained by PCR using degenerate primers. Using beta-actin as an external control, the relative liver CYP1A, GSTA, GSTR, HSP70, and ATP1A1 mRNA abundance of rabbitfish were determined by semi-quantitative RT-PCR within the exponential phase. The ratio CYP1A/beta-actin mRNA (%) of exposure group was determined to be 148.92+/-12.69, whereas the ratio of control group was 82.3+/-8.35, indicating that CYP1A was induced significantly in rabbitfish following DA exposure (P<0.05). Although the expressions of GSTA, HSP70, and ATP1A1 tended to increase and GSTR tended to decrease, no significant changes were found (P>0.05). The induction of hepatic CYP1A in response to DA suggests a potential role for fish phase I xenobiotic metabolizing enzyme in DA metabolism.
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PMID:Transcriptional responses of xenobiotic metabolizing enzymes, HSP70 and Na+/K+ -ATPase in the liver of rabbitfish (Siganus oramin) intracoelomically injected with amnesic shellfish poisoning toxin. 1821 93

Translocator protein (TSPO), formerly known as the peripheral-type benzodiazepine receptor, is an 18-kDa drug- and cholesterol-binding protein localized to the outer mitochondrial membrane and implicated in a variety of cell and mitochondrial functions. To determine the role of TSPO in ischemia-reperfusion injury (IRI), we used both in vivo and in vitro porcine models: an in vivo renal ischemia model where different conservation modalities were tested and an in vitro model where TSPO-transfected porcine proximal tubule LLC-PK(1) cells were exposed to hypoxia and oxidative stress. The expression of TSPO and its partners in steroidogenic cells, steroidogenic acute regulatory protein (StAR) and cytochrome P-450 side chain cleavage CYP11A1, as well as the impact of TSPO overexpression and exposure to TSPO ligands in vitro in hypoxia-ischemia conditions were investigated. Hypoxia induced caspase activation, reduction of ATP content, and LLC-PK(1) cell death. Transfection and overexpression of TSPO rescued the cells from the detrimental effects of hypoxia and reoxygenation. Moreover, TSPO overexpression was accompanied by a reduction of H(2)O(2)-induced necrosis. TSPO drug ligands did not affect TSPO-mediated functions. In vivo, TSPO expression was modulated by IRI and during regeneration particularly in proximal tubule cells, which do not express this protein at the basal level. Under the same conditions, StAR and CYP11A1 protein and gene expression was reduced without apparent relation to TSPO changes. Pregnenolone was identified and measured in the pig kidney. Pregnenolone synthesis was not affected by the experimental conditions used. Taken together, these results indicate that changes in TSPO expression in kidney regenerating tissue could be important for renal protection and maintenance of kidney function.
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PMID:Expression and modulation of translocator protein and its partners by hypoxia reoxygenation or ischemia and reperfusion in porcine renal models. 1938 23