scholarly journals Cortisol promotes endoplasmic glucose production via pyridine nucleotide redox

2016 ◽  
Vol 229 (1) ◽  
pp. 25-36 ◽  
Author(s):  
Zengmin Wang ◽  
Gail J Mick ◽  
Rongrong Xie ◽  
Xudong Wang ◽  
Xuemei Xie ◽  
...  
Keyword(s):  
Fasting Blood Glucose ◽  
Liver Microsomes ◽  
Glucose Production ◽  
Pyridine Nucleotide ◽  
Rat Liver Microsomes ◽  
Redox Ratio ◽  
Hepatic Glucose ◽  
Tacit Belief ◽  
Inhibition Studies

Both increased adrenal and peripheral cortisol production, the latter governed by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), contribute to the maintenance of fasting blood glucose. In the endoplasmic reticulum (ER), the pyridine nucleotide redox state (NADP/NADPH) is dictated by the concentration of glucose-6-phosphate (G6P) and the coordinated activities of two enzymes, hexose-6-phosphate dehydrogenase (H6PDH) and 11β-HSD1. However, luminal G6P may similarly serve as a substrate for hepatic glucose-6-phophatase (G6Pase). A tacit belief is that the G6P pool in the ER is equally accessible to both H6PDH and G6Pase. Based on our inhibition studies and kinetic analysis in isolated rat liver microsomes, these two aforesaid luminal enzymes do share the G6P pool in the ER, but not equally. Based on the kinetic modeling of G6P flux, the ER transporter for G6P (T1) preferentially delivers this substrate to G6Pase; hence, the luminal enzymes do not share G6P equally. Moreover, cortisol, acting through 11β-HSD1, begets a more reduced pyridine redox ratio. By altering this luminal redox ratio, G6P flux through H6PDH is restrained, allowing more G6P for the competing enzyme G6Pase. And, at low G6P concentrations in the ER lumen, which occur during fasting, this acute cortisol-induced redox adjustment promotes glucose production. This reproducible cortisol-driven mechanism has been heretofore unrecognized.

INHIBITION OF14C-ESTRONE METABOLISM IN RAT LIVER MICROSOMES BY 2-HYDROXYESTROGENS AND RELATED COMPOUNDS

1965 ◽  
Vol 43 (2) ◽  
pp. 281-290 ◽  
Author(s):  
Catherine Lazier ◽  
P. H. Jellinck
Keyword(s):  
Rat Liver ◽  
Liver Microsomes ◽  
Structural Features ◽  
Water Soluble ◽  
Rat Liver Microsomes ◽  
Synthetic Estrogen ◽  
Natural Estrogens ◽  
Water Soluble Protein ◽  
Inhibition Studies ◽  
Related Compounds

Inhibition studies with compounds having structural features in common with the natural estrogens have shown that 2-hydroxyestrone and 2-hydroxyestradiol are potent inhibitors of the rat liver microsomal system, which converts estrone to water-soluble protein-bound products. Simple phenols and naphthols hydroxylated in the ortho and para positions were also found to be good inhibitors, but the corresponding meta-hydroxylated compounds, as well as various anthraquinones and estrogens substituted in the 6, 10, or 16 positions, were inactive in this respect. The synthetic estrogen, hexestrol, lost its inhibitory activity on conversion to dihydroxy hexestrol, a nonestrogenic analogue. The type of inhibition produced by 2-hydroxyestrone, equilenin, diethylstilbestrol, and menadione has been determined by the Lineweaver–Burk method and shown to be competitive for the first three of these compounds.

Assessment of cytochrome P450 inhibition and induction potential of lupeol and betulin in rat liver microsomes

2016 ◽  
Vol 31 (2) ◽  
Author(s):  
Madhav Seervi ◽  
Shweta Lotankar ◽  
Shrikant Barbar ◽  
Sadhana Sathaye
Keyword(s):  
Cytochrome P450 ◽  
Rat Liver ◽  
Liver Microsomes ◽  
Rat Liver Microsomes ◽  
Significant Modification ◽  
Ic50 Values ◽  
Cyp 1A2 ◽  
Inhibition Studies

AbstractLupeol and betulin are triterpenoids that are majorly found in dietary substances. The aim of present study was to investigate the inhibition and induction potential of lupeol and betulin on cytochrome P450 (CYP)1A2, CYP2C11, CYP2D6 and CYP3A2 activities in rat liver microsomes.The inhibition and induction studies were conducted using ethoxy resorufin-The IC50 values in inhibition studies were found to be 59.42 μM (CYP1A2), >100 μM (CYP2C11, CYP2D6, CYP3A2) for lupeol, 52.24 μM (CYP1A2), and >100 μM (CYP2C9, CYP2D6, CYP3A2) for betulin. There was no significant modification observed in the CYP450 isoforms, indicating neither inhibition nor induction potential of lupeol and betulin.Lupeol and betulin have very low propensity to interact with CYP enzyme, suggesting no CYP inhibitory and inducing potential in rat liver microsomes.

scholarly journals Metabolic Characterization of a Tripeptide Human Immunodeficiency Virus Type 1 Protease Inhibitor, KNI-272, in Rat Liver Microsomes

1999 ◽  
Vol 43 (3) ◽  
pp. 549-556 ◽  
Author(s):  
Akiko Kiriyama ◽  
Tomoyuki Nishiura ◽  
Hirokazu Yamaji ◽  
Kanji Takada
Keyword(s):  
Human Immunodeficiency Virus ◽  
Protease Inhibitor ◽  
Rat Liver ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Liver Microsomes ◽  
Tissue Blood Flow ◽  
Rat Liver Microsomes ◽  
Immunodeficiency Virus

ABSTRACT KNI-272 is a tripeptide protease inhibitor for treating human immunodeficiency virus type 1 (HIV-1). In in vitro stability studies using rat tissue homogenates, KNI-272 concentrations in the liver, kidney, and brain decreased significantly with time. Moreover, in tissue distribution studies, KNI-272 distributed highly to the liver, kidney, and small intestine in vivo. From these results and reported physiological parameters such as the tissue volume and tissue blood flow rate, we considered the liver to be the main organ which takes part in the metabolic elimination of KNI-272. Then the hepatic metabolism of KNI-272 was more thoroughly investigated by using rat liver microsomes. KNI-272 was metabolized in the rat liver microsomes, and five metabolites were found. The initial metabolic rate constant (k metabolism) tended to decrease when the KNI-272 concentration in microsomal suspensions increased. The calculated Michaelis-Menten constant (Km) and the maximum velocity of KNI-272 metabolism (V max), after correction for the unbound drug concentration, were 1.12 ± 0.09 μg/ml (1.68 ± 0.13 μM) and 0.372 ± 0.008 μg/mg of protein/min (0.558 ± 0.012 nmol/mg of protein per min), respectively. The metabolic clearance (CLint,metabo), calculated asV max/Km , was 0.332 ml/mg of protein per min. Moreover, by using selective cytochrome P-450 inhibitors and recombinant human CYP3A4 fractions, KNI-272 was determined to be metabolized mainly by the CYP3A isoform. In addition, ketoconazole, a representative CYP3A inhibitor, inhibited KNI-272 metabolism competitively, and the inhibition constant(Ki) was 4.32 μM.

Performing resistance exercise before versus after aerobic exercise influences growth hormone secretion in type 1 diabetes

2014 ◽  
Vol 39 (2) ◽  
pp. 262-265 ◽  
Author(s):  
Jane E. Yardley ◽  
Ronald J. Sigal ◽  
Michael C. Riddell ◽  
Bruce A. Perkins ◽  
Glen P. Kenny
Keyword(s):  
Growth Hormone ◽  
Resistance Exercise ◽  
Hepatic Glucose Production ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Glucose Production ◽  
Lipid Mobilization ◽  
Gh Secretion ◽  
Hepatic Glucose

We compared growth hormone (GH) and plasma glucose (PG) levels in type 1 diabetic individuals performing aerobic before resistance exercise (AR) to when resistance exercise was performed first (RA). In AR, GH secretion declined in late exercise while it rose throughout exercise in RA, resulting in higher GH in RA versus AR at exercise completion. Higher GH during RA may support PG by increasing hepatic glucose production and lipid mobilization.

Inhibition of glucose-6-phosphate phosphohydrolase by 3-mercaptopicolinate and two analogs is metabolically directive

1993 ◽  
Vol 71 (3-4) ◽  
pp. 113-121 ◽  
Author(s):  
Ann M. Bode ◽  
James D. Foster ◽  
Robert C. Nordlie
Keyword(s):  
Nicotinic Acid ◽  
Quinolinic Acid ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Reduced Glutathione ◽  
Picolinic Acid ◽  
Liver Microsomes ◽  
Glucose Production ◽  
Metabolic Effects ◽  
Hepatic Glucose ◽  
Fasted Rats

3-Mercaptopicolinae (3-MP) blocks gluconeogenesis from lactate, pyruvate, alanine, and other substrates through its inhibition of phosphoenolpyruvate carboxykinase. Nevertheless, we observed increased glycogenesis, net glucose uptake, and glucose-6-P levels in livers perfused with glucose in the presence of 3-MP. In perfusions with 20 mM dihydroxyacetone, increased glycogenesis and decreased glucose production were observed with 3-MP. These metabolic effects suggested additional site(s) of action of 3-MP. Further studies showed that 3-MP inhibits glucose-6-P phosphohydrolase activity of intact liver microsomes. Several compounds with structural similarities to 3-MP (2-mercaptonicotinic acid, picolinic acid, cysteine, reduced glutathione, nicotinic acid, quinolinic acid, tryptophan, and pyridine) were tested for their effect on glucose-6-P phosphohydrolase activity. Two of these compounds, 2-mercaptonicotinic acid and picolinic acid, were found to inhibit. In perfusions including 7.5 mM fructose, the addition of 3-MP, 2-mercaptonicotinic acid, or picolinic acid increased glycogenesis, decreased glucose production, and increased hepatic glucose-6-P concentrations. These observations indicate that the inhibition of glucose-6-P phosphohydrolase may play a role in enhanced glycogenesis from glucose, dihydroxyacetone, and fructose in isolated livers from 48-h fasted rats perfused with 3-MP or certain sulfhydryl-containing and sulfhydryl-devoid analogs.Key words: glucogenesis, 3-mercaptopicolinate, glucose-6-P phosphohydrolase.

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