title: Suppression of phenacetin-induced methemoglobinemia by diethyldithiocarbamate and carbon disulfide and its relation to phenacetin metabolism in mice.
abstract: 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.
mesh_terms: 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*
chemical_list: D013859:Thiocarbamates; D010628:Phenetidine; D004050:Ditiocarb; D006899:Mixed Function Oxygenases; D010615:Phenacetin; D002246:Carbon Disulfide