Oxidation of N-methylthiobenzamide and N-methylthiobenzamide S-oxide by liver and lung microsomes.

The in vitro oxidation of N-[14C]methylthiobenzamide (NMTB) and N-[14C]methylthiobenzamide S-oxide (NMTBSO) by rat lung and liver microsomes was studied. In the presence of an NADPH-generating system, NMTB was rapidly converted to NMTBSO and small amounts of N-methylbenzamide (NMBA) and covalently bound metabolites (CVB). Under similar conditions, NMTBSO was converted to NMBA and CVB. Studies with metabolic inhibitors indicate that both the S-oxidation of NMTB and its further conversion to NMBA and CVB, probably via enzymatic oxidation to the S,S-dioxide, are catalyzed by both cytochromes P-450 and the FAD-containing monooxygenase (MFMO). Based on differential effects of inhibitors with lung vs liver microsomes, it would appear that in lung microsomes the MFMO plays a significantly greater role than cytochrome P-450 in the oxidation of NMTB and NMTBSO, whereas in the liver the contribution of these two pathways is more nearly equal. 1-Methyl-1-phenyl-3-benzoylthiourea, which blocks the in vivo pneumotoxicity of both NMTB and NMTBSO, also inhibited their in vitro microsomal metabolism and CVB, suggesting that these oxidations are obligatory steps in the expression of toxicity by these compounds.

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.

The acute toxicity of cyclopentadienyl manganese tricarbonyl in the rat.

The acute toxicity of cyclopentadienyl manganese tricarbonyl (CMT) was studied in Sprague-Dawley rats. CMT was found to produce convulsions and pulmonary edema. The ED50s for convulsion were 32 mg/kg (95% C.I. 24-42 mg/kg) p.o. and 20 mg/kg (95% C.I. 15-26 mg/kg) i.p. The LD50s for p.o. and i.p. administration were 22 mg/kg (95% C.I. 19-26 mg/kg) and 14 mg/kg (95% C.I. 10-20 mg/kg), respectively. Approximately 13-16% of the administered dose was recovered in the urine from 0 to 48 h post-dosing. The majority of this material was present as an organometallic form of manganese other than CMT. Phenobarbital pretreatment prevented the convulsions and pulmonary damage produced by a 50 mg/kg i.p. dose of CMT. Rats pretreated with CMT (5 mg/kg, i.p.) for 3 days exhibited convulsions but no deaths after treatment with a 34 mg/kg p.o. dose of CMT. These results suggest that CMT does not require metabolic activation to produce toxic effects, and that prior exposure to CMT produces tolerance.

Natural desensitization of exposed tooth roots in dogs.

With scanning electron microscopy, electron microprobe elemental analysis, and an objective method for eliciting responses to electrical stimuli, exposed tooth root surfaces in dogs were found to become naturally desensitized with time, perhaps because of the formation of acquired pellicle.