Dichloromethane as an inhibitor of cytochrome c oxidase in different tissues of rats.
Based on the metabolism of dichloromethane (DCM) to carbon monoxide (CO), a process mediated by cytochrome P-4502E1 (CYP2E1), cytochrome c oxidase activity was determined in different tissues of rats after DCM exposure. It is likely that binding of CO to cytochrome c oxidase is significant at low carboxyhemoglobin levels, because intracellular effects of CO depend on CO partial pressures in the tissues. Two methods of exposure were used: (1) administration of DCM, 3.1, 6.2, and 12.4 mmol/kg p.o. in Oleum pedum tauri, 10% (v/v), producing a maximum of 10% COHb 6 h after gavage, and (2) accidental scenario, i.e. rats were exposed nose-only to DCM, 250,000 ppm for 20 s, producing 3-4% COHb after 2 h. Cytochrome c oxidase activity was reduced 6 h after the high oral DCM dose in brain, lung, and skeletal muscle by 28-42% and 20 min after inhalative uptake of DCM in the brain, liver, kidney, and skeletal muscle by 42-51%. COHb formation due to DCM, 6.2 mmol/kg p.o., was completely prevented after treatment of rats with the mechanism-based inhibitor of CYP2E1, diethyl-dithiocarbamate (DDTC), using an oral dose of 32 mumol/kg. The decrease in cytochrome c oxidase activity after exposure to DCM was not evident in rats treated with this dose of DDTC. Therefore, it seems that the effect of DCM is produced by the DCM metabolite CO.
Lehnebach
A
A
Institut für Pharmakologie und Toxikologie, Bereich Umwelttoxikologie, Martin-Luther-Universität, Halle (Saale), Germany.
Kuhn
C
C
Pankow
D
D
D000280:Administration, Inhalation; D000284:Administration, Oral; D000818:Animals; D004050:Ditiocarb / Q000494:pharmacology; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D008297:Male; D008752:Methylene Chloride / Q000493:pharmacokinetics / Q000494:pharmacology*; D009928:Organ Specificity; D051381:Rats; D017208:Rats, Wistar
D008752:Methylene Chloride; D004050:Ditiocarb; D003576:Electron Transport Complex IV