Janneche Utne Skaare

Enhanced hepatotoxicity of dimethylnitrosamine by pretreatment of rats with the antioxidant ethoxyquin.

Abstract Pretreatment with a single oral dose of ethoxyquin (EMQ) (500 mg/kg) given 48 hr before dimethylnitrosamine (DMNA) and pretreatment with dietary doses (0.015% w/v) were found to enhance the elevated plasma glutamic oxaloacetic transaminase (GOT) activity induced by the ip administration of DMNA (30 mg/kg) to male rats. The increased hepatotoxicity of DMNA was confirmed by histologic evaluation. Pretreatment with EMQ caused increases in relative liver weights. These increases were reduced when DMNA was given 24 hr before measurements. Protein and cytochrome P -450 concentrations in liver were reduced by EMQ pretreatment. The observed inhibiting effect of DMNA on protein and cytochrome P -450 concentrations of rats that had received no pretreatment could not be measured following EMQ pretreatment. Concentrations of EMQ in liver and plasma varied in the range 0.2 to 1.7 ppm. Eighty to ninety-five percent of EMQ measured fluorimetrically was unchanged EMQ as determined by gas chromatography-mass spectrometry. No correlation was found to exist between the grade of necrosis and the EMQ concentration in liver and plasma. However, correlation seemed to exist between enhancement of DMNA-induced toxicity and stimulation of liver growth. It was suggested that EMQ-induced growth of some hepatic systems was not related to cytochrome P -450, and that this induction mechanism led to an increased hepatotoxicity of DMNA.