scholarly journals Effect of a single dose of dimethylnitrosamine on biosynthesis of nucleic acid and protein in rat liver and kidney

1971 ◽  
Vol 125 (4) ◽  
pp. 943-952 ◽  
Author(s):  
B. W. Stewart ◽  
P. N. Magee
Keyword(s):  
Single Dose ◽  
Rat Liver ◽  
Sucrose Density Gradient ◽  
Polymerase Activity ◽  
Hepatic Necrosis ◽  
Deficient Diet ◽  
Morphological Studies ◽  
Liver And Kidney

1. Administration of a single dose of dimethylnitrosamine to rats temporarily fed on a protein-deficient diet causes a high incidence of kidney tumours. The effect of such a dose of dimethylnitrosamine (40mg/kg body wt.) on metabolism of nucleic acids and protein in rat liver and kidneys was examined during the week immediately after administration. 2. Incorporation of [14C]leucine and [14C]orotate into hepatic macromolecules was inhibited within 5h of injection of dimethylnitrosamine, and did not recover for at least 5 days. Interpretation of these results is complicated by the concomitant extensive hepatic necrosis. 3. Renal RNA synthesis was assayed by incorporation of [14C]orotate in vivo and measurement of DNA-dependent RNA polymerase activity in vitro. Both systems indicate biphasic inhibition; minimal activity was recorded 9h and 3 days after treatment. Changes in incorporation of [14C]leucine into renal protein were similar but less marked. 4. Sucrose-density-gradient analysis of renal cytoplasmic RNA indicated increased synthesis of rRNA 24h after injection of the nitrosamine. The rate of loss of radioactivity from kidney ribosomes pre-labelled with [14C]orotate was not modified by dimethylnitrosamine. 5. Dimethylnitrosamine increased incorporation of [3H]-thymidine into renal DNA. The three distinct periods of stimulated synthesis observed are discussed, with particular reference to recently published morphological studies of the sequential development of kidney tumours induced by dimethylnitrosamine in protein-depleted rats.

Studies on the Biosynthesis of Flavin Nucleotides from 2-14C-Riboflavin by Rat Liver and Kidney

1973 ◽  
Vol 51 (6) ◽  
pp. 772-782 ◽  
Author(s):  
A. G. Fazekas ◽  
T. Sandor
Keyword(s):  
Rat Liver ◽  
Flavin Adenine Dinucleotide ◽  
Total Radioactivity ◽  
Flavin Mononucleotide ◽  
Time Intervals ◽  
Adult Rats ◽  
Liver And Kidney ◽  
Rat Liver Cytosol

2-14C-Riboflavin was injected subcutaneously into young adult rats to study the biosynthesis of flavin mononucleotide (FMN) and flavin–adenine dinucleotide (FAD) in the liver and kidneys. Animals were sacrificed at different time intervals following the administration of labelled riboflavin (RF), and radioactive flavins were determined in their tissues by a newly devised method. Both tissues accumulated radioactive riboflavin rapidly and peak levels were obtained at 90 min after the injection, when over 80% of the total radioactivity of the liver was present in FAD. At this time the liver contained 17% of the injected dose of 2-14C-RF. The kidneys contained relatively high quantities of free RF due to the concentration and urinary excretion of the vitamin.Analysis of subcellular fractions of the liver of animals injected with 2-14C-RF revealed that most of the radioactivity was present in mitochondria and nuclei. The flavin nucleotides of rat liver cytosol became progressively associated with macromolecules in vivo. However, there was no significant binding of free RF by macromolecules in blood plasma or liver cytosol.Kinetic studies and incubations with liver slices indicated that RF freely diffuses into the liver cells, is rapidly converted into FAD, and becomes attached to apoenzymes. The tissue uptake of RF and FMN formation is considerably influenced by the concentration of RF present in the system, both in vivo and in vitro.

scholarly journals Phenylhydrazine-mediated induction of haem oxygenase activity in rat liver and kidney and development of hyperbilirubinaemia. Inhibition by zinc-protoporphyrin

1984 ◽  
Vol 217 (2) ◽  
pp. 409-417 ◽  
Author(s):  
M D Maines ◽  
J C Veltman
Keyword(s):  
Rat Liver ◽  
Zinc Protoporphyrin ◽  
Serum Total Bilirubin ◽  
Potent Inducer ◽  
Oxygenase Activity ◽  
Liver And Kidney ◽  
Haem Oxygenase ◽  
Cytochrome P 450

Phenylhydrazine was found to be a potent inducer of microsomal haem oxygenase activity in rat liver and kidney, but not in spleen. The phenylhydrazine-mediated increase in haem oxygenase activity was time-dependent. Maximum activity was attained 12h after treatment in the liver, and 24h after treatment in the kidney. The increases in the activity of haem oxygenase in the liver and the kidney could be inhibited by cycloheximide. Furthermore, the increases could not be elicited by the treatment of microsomal preparations in vitro with phenylhydrazine. In consonance with the increased haem oxygenase activity, a marked increase (16-fold) was observed in the serum total bilirubin concentration in phenylhydrazine-treated rats. The mechanism of haem degradation promoted by phenylhydrazine in vivo appears to differ from that in vitro; only in the former case is bilirubin formed as the end-product of haem degradation. When rats were given zinc-protoporphyrin (40 mumol/kg) 12h before and after phenylhydrazine treatment, the phenylhydrazine-mediated increases in haem oxygenase activity in the liver and the kidney were effectively blocked. Treatment of rats in vivo with the metalloporphyrin also inhibited the activity of splenic haem oxygenase, and promoted a major decrease in the serum bilirubin levels. In phenylhydrazine-treated animals, the microsomal content of cytochrome P-450 was significantly decreased in the absence of a decrease in the microsomal haem concentration. The decrease in cytochrome P-450 content was accompanied by an increased absorption in the 420nm region of the reduced CO-difference spectrum, suggesting the conversion of the cytochrome to an inactive form. The marked depletion of cellular glutathione levels suggests that this conversion may be related to the action of active intermediates and free radicals formed in the course of the interaction of phenylhydrazine with the haem moiety of cytochrome P-450.

scholarly journals Metabolism of a glutathione conjugate of 2-hydroxyoestradiol by rat liver and kidney preparations in vitro

1970 ◽  
Vol 116 (5) ◽  
pp. 913-917 ◽  
Author(s):  
John S. Elce
Keyword(s):  
Rat Liver ◽  
Microsomal Fraction ◽  
Male Rat ◽  
Amino Group ◽  
Glutathione Conjugate ◽  
Acetyl Coenzyme A ◽  
Adult Male Rat ◽  
Liver And Kidney

Adult male rat liver and kidney preparations were incubated with (2-hydroxyoestradiol-1-yl)[35S]glutathione. The glutamic acid and glycine residues were removed by enzymes present in the kidney microsomal fraction; the liver preparations had no effect. The resulting 2-hydroxyoestradiol–cysteine conjugate was acetylated at the α-amino group by both liver and kidney homogenates fortified with acetyl-coenzyme A, but not significantly in the absence of this coenzyme, or by liver or kidney slices. These results suggest that an oestrogen–glutathione conjugate, if formed in vivo, would be converted into the corresponding mercapturic acid before excretion.

Poly(A) polymerase activity in ethionine-intoxicated rats: the relative effectiveness of disaggregated and intact polyribosomes as primers for poly(A) polymerase

1980 ◽  
Vol 58 (3) ◽  
pp. 236-242 ◽  
Author(s):  
James Dennis ◽  
Robert Kisilevsky
Keyword(s):  
Rat Liver ◽  
Enzyme Activities ◽  
Relative Effectiveness ◽  
Polymerase Activity ◽  
The State

Ethionine intoxication causes a change in the metabolism of poly(A) sequences on the 3′ OH terminus of mRNA in rat liver in vivo. In an attempt to determine the factors responsible for these changes, nuclear and cytoplasmic poly(A) polymerase activities and the state of the primer were examined in vitro. Requirements for optimal enzyme activities were determined. The nuclear and cytoplasmic enzymes had different K+, Mn2+, and poly(A) primer optima. The levels of nuclear and cytoplasmic poly(A) polymerase activity were shown to decrease following ethionine intoxication. Poly(A)+ RNA isolated from the livers of saline- and ethionine-treated rats served equally well as primers for the cytoplasmic poly(A) polymerase. Disaggregated polysomes were seven times more effective as primers than were intact polysomes. The results suggest that the mRNP particle which is released from polysomes as a result of ethionine intoxication functions better as a poly(A) polymerase primer than does the intact polysome.

Characterization of a novel non-peptide vasopressin V1 receptor antagonist (OPC-21268) in the rat

1993 ◽  
Vol 138 (2) ◽  
pp. 259-266 ◽  
Author(s):  
L. M. Burrell ◽  
P. A. Phillips ◽  
J. Stephenson ◽  
J. Risvanis ◽  
A.-M. Hutchins ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Rat Liver ◽  
Renal Medulla ◽  
Kinetic Studies ◽  
Dependent Manner ◽  
Kidney Medulla ◽  
Liver And Kidney

ABSTRACT A non-peptide, orally effective, vasopressin (AVP) V1 receptor antagonist 1-{1-[4-(3-acetylaminopropoxy) benzoyl]-4-piperidyl}-3,4-dihydro-2(1H)-quinolinone (OPC-21268) has recently been described. This paper reports the in-vitro and in-vivo characterization of OPC-21268 binding to vasopressin receptors in rat liver and kidney. OPC-21268 caused a concentration-dependent displacement of the selective V1 receptor antagonist radioligand, 125I-labelled [d(CH2)5,sarcosine7]AVP to V1 receptors in both rat liver and kidney medulla membranes. The concentration of OPC-21268 that displaced 50% of specific AVP binding (IC50) was 40±3 nmol/l for liver V1 and 15±2 nmol/l for kidney V1 receptors (mean ± s.e.m.; n = 3). OPC-21268 had little effect on the selective V2 antagonist radioligand [3H]desGly-NH29[d(CH2)5,d-Ile2,Ile4] AVP binding to V2 receptors in renal medulla membranes (IC50 >0·1 mmol/l). After oral administration to rats, OPC-21268 was an effective V1 antagonist in a time- and dose-dependent manner. Binding kinetic studies showed that OPC-21268 acted as a competitive antagonist at the liver V1 receptor in vitro and in vivo, in addition to its in-vitro competitive effects at the renal V1 receptor. OPC-21268 shows promise as an orally active V1 antagonist. Journal of Endocrinology (1993) 138, 259–266

scholarly journals β-2-Thienyl-dl-alanine as an inhibitor of phenylalanine hydroxylase and phenylalanine intestinal transport

1979 ◽  
Vol 177 (1) ◽  
pp. 347-352 ◽  
Author(s):  
Raul A. Wapnir ◽  
Gary S. Moak
Keyword(s):  
Single Dose ◽  
Phenylalanine Hydroxylase ◽  
Intestinal Transport ◽  
Enzymic Activity ◽  
Inhibitory Effects ◽  
Animal Tissues ◽  
Virtual Absence ◽  
Liver And Kidney

The inhibitory properties of β-2-thienyl-dl-alanine on rat phenylalanine hydroxylase from crude liver and kidney homogenates were assessed in vitro and in vivo, as well as its effects on the intestinal transport of phenylalanine, by using a perfusion procedure in vivo. The apparent Km for liver phenylalanine hydroxylase changed from 0.61mm in the absence of the inhibitor to 2.70mm in the presence of 24mm-β-2-thienyl-dl-alanine, with no significant change in the Vmax.. For kidney the corresponding values were 0.50 and 1.60mm respectively. A single dose of β-2-thienyl-dl-alanine (2mmol/kg) failed to inhibit phenylalanine hydroxylase in either organ. Repeated injections during a 4-day period caused a decline of the enzymic activity to about 40% of controls. Intestinal absorption of phenylalanine when perfused at 0.2–2.0mm concentration was also competitively inhibited by β-2-thienyl-dl-alanine. Its Ki value was estimated at 81mm. The limited inhibitory effects of β-2-thienyl-dl-alanine towards hepatic phenylalanine hydroxylase and phenylalanine intestinal transport, and its rapid metabolism, as suggested by the small elimination of this compound in the urine and its virtual absence from animal tissues, are factors that restrict its potential usefulness as an inducer of phenylketonuria in rats or as an effective blocker of phenylalanine absorption by the gut.

scholarly journals The effect of aflatoxin B1 on normal and cortisol-stimulated rat liver ribonucleic acid synthesis

1972 ◽  
Vol 130 (2) ◽  
pp. 619-629 ◽  
Author(s):  
G. E. Neal
Keyword(s):  
Rna Polymerase ◽  
Rat Liver ◽  
Aflatoxin B1 ◽  
Polymerase Activity ◽  
Enzymic Activity ◽  
Target Area ◽  
Receptor Sites ◽  
Rna Polymerase Activity

1. Aflatoxin B1, administered in vivo, inhibits the incorporation of [14C]orotic acid in vivo into rat liver nuclei, and also inhibits both Mg2+- and Mn2+-dependent RNA polymerase activities in nuclei assayed in vitro. 2. Aflatoxin B1 inhibits the cortisol-induced increase in incorporation of [14C]leucine in vivo, but does not affect the control value of this activity. 3. Aflatoxin B1 administered in vivo inhibits the increase in nuclear Mg2+-dependent RNA polymerase activity, assayed in vitro, which results from the treatment with cortisol. 4. Adrenalectomy causes a decrease in Mg2+-dependent RNA polymerase activity. The effect on this enzymic activity of adrenalectomy plus treatment with aflatoxin B1 is no greater than that of treatment with aflatoxin B1 alone. 5. These results suggest that the inhibition of cortisol-stimulated biochemical pathways by aflatoxin B1 is due to an inhibition of cortisol-stimulated RNA synthesis. 6. The cytoplasmic action of aflatoxin is thought to be due to a competition for receptor sites on the endoplasmic reticulum between steroid hormones and aflatoxin B1. No evidence was obtained for a similar competition for nuclear receptor sites between [3H]cortisol and aflatoxin B1. 7. No differences were observed between the activities of RNA polymerase preparations solubilized from control or aflatoxin-inhibited nuclei. 8. No differences in ‘melting’ profiles were observed between DNA and chromatin preparations isolated from control nuclei or from aflatoxin-inhibited nuclei. 9. It is suggested that aflatoxin B1 exerts its effect on RNA polymerase by decreasing the template capacity of the chromatin and that the aflatoxin ‘target’ area of the chromatin includes that region which is stimulated by cortisol. This process, however, does not involve inhibiting the movement of cortisol from the outside of the hepatic cell to the nuclear chromatin.

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