HEPATIC ACUTE-PHASE RESPONSE TO 3-ALKYL-2-PHENYL-2-HYDROXY-MORPHOLINIUM CATIONS

摘要

Morpholine, a local anesthetic and antiseptic is known for its toxicity and mutagenicity to humans. A facile synthesis of 3-alkyl-2-phenyl-2-hydroxymorpholinium cations was employed and products were used in a study of the acute-phase response (APR) to their long-term ingestion by rats. The chain length of the 3-alkyl groups ranged between 0 and 16 carbons as confirmed by FAB mass spectrometry and ~(13)C-NMR as well as protons, NMR. These morpholinium cations, especially those with long alkyl chains, are expected to show inhibition of mitochondrial carnitine palmitoyltransferase. The morpholinium cations were subcutaneously administered to rats (1 mmole/kg) to follow the kinetics of hepatic APR to a single application. The APR kinetics resembled those of CCl4 which suggests that the toxicity of morpholinium ions is most likely mediated by leukocyte endogenous mediator and/or kinins and that their possible elimination by binding to APR proteins, is followed by regression of the spectrum of APR to aseptic control. Furthermore, consumption of drinking water supplemented with 1 mM morpholinium cations over a period of one month resulted in a hepatic APR characteristic of the cirrhosis developed upon consuming thioacetamide or a combination of acetominophen and ethanol. Cirrhotic livers of rats failed to regenerate to their original weight when 75% partially hepatectomized due to irreversible damage to hepatic infrastructure.