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Alterations of hepatic drug metabolising system due to dimethylformamide (DMF)
K Fujishiro1, K Imazu, Y Makita
1Occupational Health Training Center, University of Occupational and Environmental Health, Kitakyushu.
Abstract:
The effect of repeated exposures to N, N-dimethylformamide (DMF) on the liver and the hepatic microsomal monooxygenase system and glutathione metabolizing enzymes were investigated. DMF was administered to Wistar male rats by subcutaneous (s.c.) injection at 1.0 ml/kg body weight (950 mg/kg), 3 times a week for 2 weeks. The gain in the body weight in the DMF group were suppressed compared with the control group at 2 week. The relative weight of the liver, spleen and kidney also appeared to increase in the DMF group as same as in the control group. Hematological examinations showed no changes. Glutamic oxaloacetic transaminase (GOT) and glutamic pyruvic transaminase (GPT) did not change in the DMF group. Hepatic microsomal protein and cytochrome P-450 did significantly decrease by 30% and 38%, respectively, while there was no change in cytochrome b5, NADPH-cytochrome c reductase and NADH-ferricyanide reductase. Glutathione peroxidase (GPx) activity was not affected by DMF administration, while glutathione reductase (GR) and glutathione S-transferase, (GST) activity were significantly increased by 16% and 64%, respectively. These results indicate that DMF alters tke hepatic drug metabolizing system without significant increase of the serum transaminase levels. These findings may contribute to elucidate the mechanism of DMF hepatotoxicity.
Insights
Repeated N, N-dimethylformamide (DMF) exposure in rats altered liver drug metabolism, decreasing cytochrome P-450 and increasing glutathione enzymes. These changes occurred without significant increases in serum transaminase levels, suggesting a specific mechanism for DMF hepatotoxicity.
Area of Science:
- Toxicology
- Hepatology
- Biochemistry
Background:
- N, N-dimethylformamide (DMF) is an industrial solvent with potential toxic effects.
- Understanding DMF's impact on liver function and metabolism is crucial for occupational safety.
Purpose of the Study:
- To investigate the effects of repeated N, N-dimethylformamide (DMF) exposure on the liver and associated enzyme systems in rats.
- To elucidate the mechanisms underlying DMF-induced hepatotoxicity.
Main Methods:
- Wistar male rats were administered DMF (1.0 ml/kg) subcutaneously, three times weekly for two weeks.
- Evaluated body weight, relative organ weights, hematology, serum transaminases (GOT, GPT), and hepatic enzyme activities (cytochrome P-450, b5, reductase, glutathione peroxidase, reductase, and S-transferase).
Main Results:
- DMF exposure suppressed body weight gain and increased relative liver, spleen, and kidney weights.
- Significant decreases in hepatic microsomal protein (30%) and cytochrome P-450 (38%) were observed.
- Glutathione reductase (16%) and glutathione S-transferase (64%) activities significantly increased, while glutathione peroxidase remained unchanged. Serum transaminases showed no significant alterations.
Conclusions:
- Repeated DMF exposure alters the hepatic drug-metabolizing system, specifically impacting cytochrome P-450 and glutathione metabolism.
- The observed changes in enzyme activities, without elevated transaminases, suggest a distinct pathway for DMF hepatotoxicity.
- These findings contribute to understanding the toxicological mechanisms of DMF in the liver.