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

Skaare, Janneche Utne; Nafstad, Inger; Dahle, Hans Kolbein

doi:10.1016/0041-008x(77)90193-4

Cited by 14 publications

(5 citation statements)

References 30 publications

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“…The high and persisting radioactivity in the liver suggests that metabolism of ethoxyquin takes place in this organ. The gap found between the amount in liver of unmetabolized ethoxyquin, 0.01 % of oral dose after 3 days (Skaare et a/. 1977), and ethoxyquin plus metabolites, 0.5 and 0.2% of oral dose after 2 and 6 days respectively (table I), also supports the view concerning the role of the liver in the metabolism of ethoxyquin.…”

Section: Discussionsupporting

confidence: 71%

The Distribution of ¹⁴C‐Ethoxyquin in Rat

Skaare¹,

Nafstad²

1979

Acta Pharmacologica et Toxicologica

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Adult male rats were given the antioxidant ''C-ethoxyquin by oral intubation and were sacrificed at various time intervals from 0.5 hr to 6days following administration of the drug. The distribution pattern was studied by whole-body autoradiography and liquid scintillation counting. The isotopelabelled antioxidant was distributed throughout most tissues and the blood at 0.5 hr after administration. The highest radioactivity throughout the experimental period was observed in the liver, the kidney, the gastrointestinal tract and the adipose tissue. No activity was observedin the brain and the central nervous system. Ofthe dose ingested 2.2 and 0.2% were found in the liver at 0.5 hr and 6 days respectivelyfollowing dosing. The hepatic peak in radioactivity was measured at 8 hrs and after 6 days 7.5% of this level was still present in the liver. Six days after administration residues of ethoxyquin and metabolites were also present in the kidney cortex, the intestines, the lung, various adipose tissue and blood.

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Section: Discussionsupporting

confidence: 71%

The Distribution of ¹⁴C‐Ethoxyquin in Rat

Skaare¹,

Nafstad²

1979

Acta Pharmacologica et Toxicologica

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“…Under our experimental conditions, the tendencies observed were that EMQ (Skaare et al 1977) and selenium slightly enhanced, while vitamin E ameliorated the acute hepatotoxicity of DMNA. The mechanisms by which these compounds affect the hepatocellular damage of DMNA are not clear and the following suggestions are put forward.…”

Section: Discussionmentioning

confidence: 61%

“…1974 a, b;Kahl & Netter 1977), however, Skaare et al (1977), did not detect any enzyme-inducing effect by protein and cytochrome P-450 analyses. Ultrastructural observations of smooth endoplasmic reticulum proliferation in rat liver cell after EMQadministration (Nafstad & Skaare 1977) combined with reduction of protein synthesis in the same rats indicated that EMQ belonged to the group of substances that are potential enzyme inducers but the metabolites of which exert a blocking effect in protein synthesis (Meldolesi 1967). It has been suggested that it is EMQ's effect on some hepatic enzyme system not related to cytochrome P-450 that causes enhancement of the acute necrotizing actions of DMNA (Skaare et at.…”

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confidence: 99%

Interaction of Vitamin E and Selenium with the Hepatotoxic Agent Dimethylnitrosamine

Skaare¹,

Nafstad²

1978

Acta Pharmacologica et Toxicologica

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Pretreatment of rats with vitamin E, 0.02% w/w of the diet and a sc dose, 200 mg/kg, given 48 hrs. before dimethylnitrosamine, DMNA, was found to ameliorate the acute hepatotoxicity of DMNA (30 mg/kg) as reflected in reduced plasma asparagine‐amino‐transferase (AspAT) activity. This effect was confirmed by histological evaluation. No significant effect of DMNA on plasma levels of vitamin E was observed, however, DMNA significantly increased the hepatic level of vitamin E supplemented rats. Pretreatment with selenium, 0.5 mg/kg given intraperitoneally 48 hrs. before DMNA, was found to enhance the acute hepatotoxicity of DMNA as reflected in increased elevation of plasma AspAT activity. This effect was not confirmed morphologically. DMNA did not have any effect on the hepatic selenium state in selenium pretreated rats; however, selenium pretreatment tended to decrease hepatic and plasma tocopherol levels. To explain the effects observed in the present investigation, various mechanisms were discussed. If the compounds were acting as antioxidants, then the difference in intracellular localization had to be important. More likely a specific biochemical function involving drug metabolizing enzymes could be involved. Finally vitamin E could protect membranes from damage during the necrotizing action of DMNA.

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“…Liver enlargement and induction of drug metabolizing enzymes was observed in rats exposed to EQ at 5 g/kg of feed for 14 days; however, liver weights returned to normal values 30 days after withdrawal of EQ, indicating reversibility of the hepatic changes (43). Although EQ seems to reduce the toxic effects of a range of compounds, it can also increase the potency of compounds such as dimethylnitrosamine, manifested as increased liver weight/body weight ratios, increased plasma glutamic oxaloacetic transaminase activity, and liver necrosis (49). In the present study, no indication of liver malfunction was observed, suggesting that the dose used in the present study did not cause any adverse effects in F344 rats.…”

Section: Discussionmentioning

confidence: 75%

Investigations on the Metabolism and Potentially Adverse Effects of Ethoxyquin Dimer, a Major Metabolite of the Synthetic Antioxidant Ethoxyquin in Salmon Muscle

Ørnsrud¹,

Arukwe

Bohne

et al. 2011

Journal of Food Protection

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The feed additive ethoxyquin (EQ) is a commonly used synthetic antioxidant preservative in animal feeds. In farmed Atlantic salmon fillets, EQ residues are present, both as the parent compound and as EQ derivatives. One of the main EQ derivates in fish muscle is an ethoxyquin dimer (EQDM), and the potential toxicity of this metabolite is not known. The aim of this study was to evaluate the metabolism and potentially toxicological effects of EQDM. A 90-day subchronic exposure study with repeated dietary exposure to EQDM at 12.5 mg/kg of body weight per day was performed with male F344 rats. Hepatic Cyp1a1 mRNA was significantly reduced to <3% of the control in rats fed EQDM, and hepatic Cyp2b1 mRNA was increased to 192%. EQDM increased Gstpi1 mRNA expression to 144% that of the control, but the activity level of this phase II enzyme was reduced. Biomarkers of liver and kidney function did indicate adverse effects of EQDM when F344 rats were fed 12.5 mg/kg of body weight per day. The present study revealed that EQDM produces responses that are comparable to those produced by the parent compound (EQ) in terms of activating the same enzyme systems.

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

Cited by 14 publications

References 30 publications

The Distribution of ¹⁴C‐Ethoxyquin in Rat

The Distribution of ¹⁴C‐Ethoxyquin in Rat

Interaction of Vitamin E and Selenium with the Hepatotoxic Agent Dimethylnitrosamine

Investigations on the Metabolism and Potentially Adverse Effects of Ethoxyquin Dimer, a Major Metabolite of the Synthetic Antioxidant Ethoxyquin in Salmon Muscle

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

Cited by 14 publications

References 30 publications

The Distribution of 14C‐Ethoxyquin in Rat

The Distribution of 14C‐Ethoxyquin in Rat

Interaction of Vitamin E and Selenium with the Hepatotoxic Agent Dimethylnitrosamine

Investigations on the Metabolism and Potentially Adverse Effects of Ethoxyquin Dimer, a Major Metabolite of the Synthetic Antioxidant Ethoxyquin in Salmon Muscle

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The Distribution of ¹⁴C‐Ethoxyquin in Rat

The Distribution of ¹⁴C‐Ethoxyquin in Rat