Effect of various compounds on the reaction of tris-(2-chloroethyl)amine with ribonucleic acid in vitro and on its toxicity in mice.
The effect of tris-(2-chloroethyl)-amine (HN-3) on RNA and DNA was investigated spectrophotometrically. The shift in the absorbance spectrum caused by the addition of HN-3 was used to test a variety of compounds for their ability to inhibit RNA alkylation. The effect of HN-3 on the activity of several enzymes was also investigated. The activities of ribonuclease A, desoxyribonuclease I, acetylcholinesterase, diaphorase, glutathione reductase, adenosine desaminase, glyoxalase I, 3-hydroxyacyl-CoA-dehydrogenase, xanthine oxidase, glucose-6-phosphate dehydrogenase, hexokinase and the microsomal N-oxygenation of aniline were not changed by HN-3, whereas the activity of cytochrome-c-reductase exhibited a dose dependent diminution in the presence HN-3. Of 105 compounds tested only 14, namely, sodium thiosulfate, dithioxanthine, thiosalicylic acid, 1,2,4-triazole-5-thiol, 2-thiocytosine, 2-thiohistadine, 2,3-dithiosuccinic acid, thioglycolic acid, 3-mercapto-D-valine,6-amino-2-thiouracil, thionicotine amide, dithiothreitol, sodium sulfite, and ergothioneine prevented the alkylation of RNA. All of them also reacted with HN-3 in absence of RNA. No correlation was found between the reaction constant of the reaction compound:HN-3 in the absence of RNA and the concentration of the compound which inhibited RNA alkylation by 50%. The compounds which were effective in vitro were also tested in mice for their ability to reduce HN-3 toxicity in vivo. Only sodium thiosulfate, d-penicillamine, and dithiosuccinic acid were effective. A 3.9fold increase in the LD50 of HN-3 was achieved in mice treated with sodium thiosulfate 3330 mg/kg i.p., a 1.7fold with 2125 mg dithiosuccinic acid/kg, and a 2fold increase with 2500 mg/kg d-penicillamine. The compound tested was injected i.p. 0.5 to 1 min after the s.c. injection of HN-3.
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D004247:DNA / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D004791:Enzyme Inhibitors; D066298:In Vitro Techniques; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D009588:Nitrogen Mustard Compounds / Q000494:pharmacology* / Q000633:toxicity; D012313:RNA / Q000378:metabolism*; D012260:Ribonucleases / Q000378:metabolism
D000477:Alkylating Agents; D004791:Enzyme Inhibitors; D009588:Nitrogen Mustard Compounds; C009802:2,2',2''-trichlorotriethylamine; D012313:RNA; D004247:DNA; D003851:Deoxyribonucleases; D012260:Ribonucleases