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Strain differences in tissue repair response to 1,2-dichlorobenzene (1996)

Kulkarni, Swarupa G. ; Duong, Hoan ; Gomila, Remi ; [et al.]

Springer

Archives of toxicology 70 (1996), S. 714-723

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ISSN: 1432-0738

Keywords: Key words 1 ; 2-Dichlorobenzene (o-DCB) ; Straindifferences ; Dose-response ; Tissue repair ; Ultimate outcome

Source: Springer Online Journal Archives 1860-2000

Topics: Medicine

Notes: Abstract Fischer 344 (F344) rats are reportedly 75-fold more sensitive than Sprague Dawley (S-D) rats to 1,2-dichlorobenzene (o-DCB) hepatotoxicity. Lethality studies were conducted since no information was available regarding the ultimate consequence of this sensitivity in terms of animal survival in the two strains. LD50s for o-DCB (1.66 ml/kg and 1.76 ml/kg in male F344 and S-D rats, respectively) did not differ. Several studies have shown the importance of tissue repair on animal survival following exposure to toxic chemicals. The objective of this study was to investigate if differential rates of cell division and tissue repair might explain the lack of difference in LD50 dose between the two strains despite higher hepatotoxic injury in F344 rats. Age-matched male S-D and F344 rats were administered o-DCB (0.2, 0.6, 1.2 ml/kg, i.p.); injury and tissue repair occurring as two dynamic but opposing events were measured over time. Liver injury was assessed by measuring plasma alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities and by liver histopathology. Higher plasma ALT elevations were observed in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. Using SDH as a marker of liver injury, the strain difference was evident only at 0.2 ml o-DCB/kg. Liver regeneration was estimated by 3H-thymidine incorporation into hepatonuclear DNA and via proliferating cell nuclear antigen (PCNA) assay. Prompt and significantly higher hepatocellular regeneration beginning at 36 h was evident in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg. The significantly higher depletion of hepatic glycogen observed in F344 rats following administration of 0.2 and 0.6 ml o-DCB/kg occurred without significant changes in plasma glucose and is consistent with highly stimulated tissue repair seen in these rats at the corresponding doses. However, increasing the dose further to 1.2 ml o-DCB/kg results in a delayed (S-phase synthesis begins at 48 h) and diminished response to o-DCB. These findings suggest that a significantly higher rate of tissue repair in F344 rats helps them overcome higher liver injury inflicted by o-DCB. This differential in tissue repair in the two strains may play a vital role in equalizing the ultimate outcome of toxicity in the two strains.

Type of Medium: Electronic Resource

URL: http://dx.doi.org/10.1007/s002040050332

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Effect of amiodarone on Na+-, K+-ATPase and Mg2+-ATPase activities in rat brain synaptosomesA report of these findings was made at the 25th annual conference of the Society of Toxicology, March 3-7, 1986, at New Orleans, LA. (1986)

Rao, K. S. Prasada ; Rao, S. B. ; Camus, Ph. ; [et al.]

New York, NY [u.a.] : Wiley-Blackwell

Cell Biochemistry and Function 4 (1986), S. 143-151

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ISSN: 0263-6484

Keywords: Amiodarone neuropathy ; Na-, K-ATPase ; Mg2-ATPase ; rat brain synaptosomes ; p-nitrophenyl phosphatase ; ion transport in CNS ; ATP turnover in CNS ; ouabain binding ; Chemistry ; Biochemistry and Biotechnology

Source: Wiley InterScience Backfile Collection 1832-2000

Topics: Biology , Medicine

Notes: Amiodarone hydrochloride is a diiodinated antiarrhythmic agent widely used in the treatment of cardiac disorders. With the increasing use of amiodarone, several untoward effects have been recognized and neuropathy following amiodarone therapy has recently been reported. The present studies were carried out to study the effect of amiodarone on rat brain synaptosomal ATPase in an effort to understand its mechanism of action. Na+, K+-ATPase and oligomycin sensitive Mg2+ ATPase activities were inhibited by amiodarone in a concentration dependent manner with IC50 values of 50 μM and 10 μM respectively. [3H]ouabain binding was also decreased in a concentration dependent manner with an IC50 value of 12 μM, and 50 μM amiodarone totally inhibited [3H]ouabain binding. Kinetics of [3H]ouabain binding studies revealed that amiodarone inhibition of [3H]ouabain binding is competitive. K+-activated p-nitrophenyl phosphatase activity showed a maximum inhibition of 32 per cent at 200 μM amiodarone. Synaptosomal ATPase activities did not show any change in rats treated with amiodarone (20mg kg-1 day-1) for 6 weeks, when compared to controls. The treatment period may be short, since the reported neurological abnormalities in patients were observed during 3-5 years of treatment. The present results suggest that amiodarone induced neuropathy may be due to its interference with sodium dependent phosphorylation of Na+, K+-ATPase reaction, thereby affecting active ion transport phenomenon and oxidative phosphorylation resulting in low turnover of ATP in the nervous system.

Additional Material: 9 Ill.