METABOLISM OF RAT-KIDNEY NUCLEI 527 2. The nuclei in vitro incorporate [2-14C]glycine and [1-14C]valine into nuclear protein and [6-14C]orotic acid and [8-14C]adenine into nucleic acids. 3. Anoxia and 2,4-dinitrophenol inhibit the incorporation of the radioactive precursors into nuclear proteins and nucleic acids. Chlorpromazine inhibits the incorporation of valine, but has no effect on the incorporation of orotic acid. 4. The specific activities of adenosine triphosphatase, succinoxidase, cytochrome oxidase, DPNHcytochrome c reductase, DPNH-neotetrazolium reductase and lactic dehydrogenase are reported. Evidence suggesting that succinoxidase activity is due to mitochondrial contamination whereas cytochrome oxidase is a true nuclear component is presented. 5. The chemical composition and metabolism of rat-kidney nuclei and rat-liver nuclei are compared.
Rats have been given a single dose of trimethyltin (10 mg/kg) and the intracellular events have been followed particularly in hippocampus, cerebral cortex, cerebellum and spinal ganglion cells. The earliest change visible occurs 12 h after this dose and is found to be dense membrane-bound bodies, probably derived from branching tubulo-vesicular smooth endoplasmic reticulum formations. These occur in close connection with rought endoplasmic reticulum and polyribosomes and appear also to have some association with the Golgi complex. At 24 h there is a general vacuolation of Golgi cisterns and SER membranes, and the membrane-bound dense body formation is greatly increased. SER abnormalities are particularly conspicuous in Purkinje cells. In spinal ganglion cells, while vacuolation of Golgi cisterns is intense, dense bodies are inconspicuous and are replaced by increased autophagosomes, often of great complexity. By 48 h vacuolation of Golgi cisterns has waned, but accumulation of dense bodies and secondary lysosomes has steadily increased. In spinal ganglion cells autophagosomes only are increased as the Golgi vacuolation declines. At later times steady increases of lysosomal dense bodies is seen generally accompanied in hippocampal pyramidal cells and dentate fascia cells by abundant cell death. The suggestion is put forward that the Golgi complex may be the seat of the critical metabolic lesion and disturbances to protein transfer and protein synthesis follow. No explanation for the selective loss of hippocampal h1-5 (CA1-CA4 except Sommer's sector) pyramidal cells and of small dentate fascia neurons can be derived from these conclusions.
A number of phosphorothionate (P = S) insecticides, including bromophos and fenitrothion, prevent trialkyl phosphorothiolate (P = O)-induced lung toxicity and the resulting increase in lung weight normally observed at 3 days in the rat. Measurement of 7-ethoxycoumarin O-deethylase (7-EC) activity after both phosphorothionate and phosphorothiolate dosing revealed differing patterns of loss of enzyme activity. Depletion of 7-EC activity by phosphorothionates was maximal between 2 and 10 h after dosing, with recovery between 24 and 72 h. Phosphorothiolates, however, appear to cause two phases of loss of 7-EC activity, an initial fall of approximately 30% observed at 2 h and a secondary fall, maximal on day 3, with loss of 97% of activity, apparently associated with the pathological changes in the lung. It is suggested that oxidative metabolism of phosphorothionates known to occur at the P = S moiety, with suicidal loss of P-450, may then prevent oxidative activation of an S-methyl on the phosphorothiolates, the most likely site for production of a reactive intermediate capable of damaging the lung. Lung 7-EC in rat is sensitive to concentrations of the phosphorothionates bromophos and fenitrothion at 5-25 times less than those causing loss of liver 7-EC activity and at doses 125-600 times less than their LD50s. If repeated in man this may have implications for personnel occupationally exposed to these compounds.
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