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Studies were conducted on the stimulatory effect that various nucleic-acid-binding compounds have on the hydrolysis of RNA and polyribonucleotides by pancreatic ribonuclease A and by other ribonucleases. The stimulatory activity of chloroquine on tRNA hydrolysis by pancreatic ribonuclease was due to the formation of oligonucleotides of a wide range of sizes and was not due to the formation of very short ( n greater than 5) oligonucleotide fragments of tRNA. The dextrorotatory and levorotatory isomers of chloroquine did not differ in their ability to stimulate the hydrolysis of tRNA by pancreatic ribonuclease A. In addition to chloroquine and primaquine, other nucleic-acid-binding compounds (e.g., quinacrine, lucanthone, and proflavin) stimulated the hydrolysis of tRNA by pancreatic ribonuclease A. Chloroquine did not alter the rate of hydrolysis by pancreatic ribonuclease A of low-molecular-weight substrates (cytidine cyclic 2':o'-monophosphate, uridine cyclic 2':3'-monophosphate, cytidylyl-adenosine, or uridylyl-uridine). Furthermore, chloroquine and primaquine did not affect the hydrolysis of poly(A) by high concentrations of pancreatic ribonuclease A. In studies on the hydrolysis of tRNA by other endoribonucleases, several of the nucleic-acid-binding compounds (e.g., quinacrine and ethidium) exhibited appreciable inhibition of both ribonuclease N1 and ribonuclease T1. None of the compounds tested stimulated the activity of ribonuclease T1, and only chloroquine, and perhaps lucanthone, stimulated the hydrolysis of tRNA by ribonuclease N1.

The distribution of primaquine was measured in seven rat tissues at 15-180 min after the intraperitoneal injection of the antimalarial 8-aminoquinoline. The half-life of unmetabolized primaquine was 4.0 h in lung, 1.7-1.9 h in blood, spleen, kidney and heart, and 1.2 h in liver. At each interval, the concentrations of unmetabolized primaquine were (in order): lung greater than liver, kidney, spleen greater than heart greater than brain greater than or equal to blood. At 3 h after the injection of [6-O-methyl-3H]primaquine, unmetabolized primaquine constituted 10% of the total 3H in blood and 40-60% of the total 3H in liver, brain, heart and kidney.

The intraperitoneal administration of PtCl4 or Pd(NO3)2 at levels of 28 or 56 mumole/kg body weight decreased the thymidine incorporation into DNA of spleen, liver, kidney, and testis. Spleen was most sensitive to both the platinum and the palladium salt. In liver, DNA syntheses in parenchymal cells and stromal cells were about equally sensitive to PtCl4. In control rats, only 20-30% of the 3H in the acid-soluble fraction of liver or spleen was in the form of thymidine and its phosphate esters 2 hr after the intraperitoneal injection of 3H-thymidine; prior injection of PtCl4 (56 mumol/kg body weight) did not change the pattern.

The effects of various salts of platinum of palladium were determined on the parameters of the microsomal mixed-function oxidase system from rat liver. The intraperitoneal injection of PtCl4 or Pd(NO3)2 increased the hexobarbital-induced sleeping time in vivo and generally decreased the aminopyrine demethylase and the content of cytochrome P-450 in isolated hepatic microsomes. The dietary administration of various salts of platinum or palladium for 1 wk generally decreased or had no effect on the parameters of drug metabolism by isolated microsomes and after 4 or more wk generally had no effect on, or increased, the parameters. The addition of 0.15-0.2 mM PtCl4 or 0.2-0.3 mM Pd(NO3)2 to the incubation medium (containing 5 mM MgCl2) inhibited the aminopyrine demethylase of isolated hepatic microsomes by 50%.

1 Chloroquine, primaquine and ethidium inhibitied thymidine incorporation into deoxyribonucleic acid of rat tissues when administered concurrently with the labelled precursor. 2 Chloroquine and primaquine inhibited the incorporation of uridine and adenine, but not orotate, into various ribonucleic acid fractions of liver of rats and mice. These drugs had no effect on leucine incorporation into hepatic protein in rats or mice. 3 Although chloroquine and primaquine are active against different stages in the life cycle of the malarial parasites, the two aminoquinolines exert similar effects in rodent tissues.

Preliminary studies have been conducted on various parameters in order to assess the possible and relative toxicities of a number of metallic salts. Upon oral administration in lethal-dose experiments, two soluble Pt4+ salts were more toxic than the other salts tested. Following intraperiotneal injection in lethal-dose experiments, PbCl2 was less toxic than several of the soluble or partially soluble salts of Pt4+, Pd2+, and Mn2+. An intake of a total of approximately 250 mg of Pt4+ per rat in the drinking fluid over a 30-day interval did not affect the activities of aniline hydroxylase and aminopyrine demethylase in rat liver microsomes. In rats receiving soluble Pt4+ salts in the drinking fluid, the highest concentration of Pt was found in the kidney and an appreciiable concentration was found in the liver.

Rat liver nuclei, after preliminary isolation in 2.2 molar sucrose solution, were separated into density classes by centrifugation at 95,000 g for 45 to 85 minutes in a sucrose density gradient (density range, 1.28 to 1.33). Nuclei from normal liver separated into three bands with average DNA phosphorus content per nucleus of 0.67, 0.84, and 0.93 picogram for top, middle, and bottom bands, respectively. Nuclei from regenerating liver (26 hours after one-third hepatectomy) yielded three bands and a pellet fraction with average DNA phosphorus content per nucleus of 0.76, 1.02, 1.38, and 1.51 picograms (top to bottom of tube). This method appears capable of yielding nuclei which have increased their DNA content prior to mitosis, and this procedure should be valuable in studies of biochemical changes which occur in nuclei preparing for mitosis.