The role of metabolism in N-methylthiobenzamide-induced pneumotoxicity.
N-Methylthiobenzamide (NMTB) produces pulmonary edema, hydrothorax, and death in rodents. The objectives of the present studies were to establish a relationship between the lethality of NMTB and its pneumotoxicity and to explore the role of S-oxidation in these events. Pulmonary injury was assessed by measuring [14C]thymidine incorporation into pulmonary DNA. Administration of NMTB resulted in increased pulmonary [14C]thymidine incorporation in both rats and mice. These increases were blocked in both species by pretreatment of animals with sublethal doses of NMTB. However, the lethality of NMTB was not blocked in mice by prior administration of NMTB even though this procedure has been shown to protect rats. 1-Methyl-1-phenyl-3-benzoylthiourea (MPBTU) protected both rats and mice from lethal doses of NMTB and blocked NMTB-induced increases in pulmonary [14C]thymidine incorporation. N-Methylthiobenzamide S-oxide (NMTBSO), a metabolite of NMTB, produced lung injury which was similar to that produced by NMTB. NMTBSO was more potent than NMTB when administered iv, but not when given ip. The role of hepatic metabolism in NMTB pneumotoxicity was examined by administering NMTB to rats which had either undergone partial hepatectomy or been pretreated with N-octylimidazole. Neither of these procedures diminished the lethality of NMTB. These data suggest that NMTB lethality is mediated by pulmonary injury resulting from NMTB S-oxidation in the lung.
D000577:Amides / Q000633:toxicity*; D000818:Animals; D002250:Carbon Radioisotopes; D004247:DNA / Q000378:metabolism; D004347:Drug Interactions; D006498:Hepatectomy; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007928:Lethal Dose 50; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013854:Thioamides / Q000378:metabolism / Q000633:toxicity*; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism
D000577:Amides; D002250:Carbon Radioisotopes; D013854:Thioamides; C046800:1-methyl-1-phenyl-3-benzoylthiourea; C046391:N-methylthiobenzamide; D004247:DNA; D013890:Thiourea; D013936:Thymidine