Suppression of phenacetin-induced methemoglobinemia by diethyldithiocarbamate and carbon disulfide and its relation to phenacetin metabolism in mice.
Oral pretreatment with diethyldithiocarbamate (DTC) and carbon disulfide (CS2) prevented mice from methemoglobinemia induced by phenacetin. This treatment resulted in marked elevation of plasma p-phenetidine concentrations, prolongation of phenacetin levels, and lowering of N-acetyl-p-aminophenol and p-aminophenol levels. Both DTC and CS2 also suppressed p-phenetidine-induced methemoglobinemia with a delay in plasma p-phenetidine disappearance. In vitro, methemoglobin formation by p-phenetidine was decreased in liver microsomes isolated from DTC- or CS2-treated mice. The liver microsomal phenacetin and p-phenetidine O-deethylation activities and p-phenetidine N-hydroxylation activity decreased 1 h after administration of DTC or CS2, whereas deacetylation of phenacetin and N-acetyl-p-aminophenol by microsomes and acetylation of p-phenetidine by a soluble fraction from a liver homogenate were scarcely affected. The suppression of methemoglobinemia by DTC and CS2 may result from an inhibition of metabolic conversion of p-phenetidine to methemoglobin-forming substances such as N-hydroxy-p-phenetidine which is of most importance, p-aminophenol and 2-hydroxy-p-phenetidine by the microsomal cytochrome P-450-containing monooxygenase system in the liver.
D000818:Animals; D001711:Biotransformation; D002246:Carbon Disulfide / Q000494:pharmacology*; D003640:Dealkylation; D004050:Ditiocarb / Q000494:pharmacology*; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced / Q000517:prevention & control*; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010615:Phenacetin / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D010628:Phenetidine / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology*
D013859:Thiocarbamates; D010628:Phenetidine; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; D010615:Phenacetin; D002246:Carbon Disulfide