SUPPRESSION OF PHENACETIN-INDUCED METHEMOGLOBINEMIA BY DIETHYLDITHIOCARBAMATE AND CARBON DISULFIDE AND ITS RELATION TO PHENACETIN METABOLISM IN MICE

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Oral pretreatment with diethyldithiocarbamate (DTC) and carbon disulfide (CS_2) 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 CS_2 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 CS_2-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 CS_2,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 CS_2 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.
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