The Metabolism and Liver Toxicity of N, N-dimethylformamide in the Isolated Perfused Liver

Koh, Sang Baek; Cha, Bong Suk; Kang, Myung Guen; Koh, Sang Yeol; Lee, Jung Woo; Kwon, Sang Ok

Abstract

N, N-dimethylformamide (DMF) is a solvent which is widely used in the industrial workplace. It causes the liver damages to the chronically exposed workers and is also well known as the harzadous material to generate occupational malignancies. DMF is mainly metabolized into N-hydroxymethyl-N-methylformamide (HMMF) by the microsomal cytochrome p-450. HMMF breaks down to NMF. However, the detailed mechanism of its toxicity are unknown. In this experiment, the metabolism and the toxicity of DMF was investigated using an isolated perfumed liver model. DMF (0, 10, 25mM) were added into recirculating perfusate of the isolated perfused rat liver. Samples were collected at 0, 30, 45, 60, 75, 90 minutes from inferior vena cava. The gas-chromatography was used to analyze the metabolite of DMF, The changes in the oxygen consumption rate by DMF were monitored during perfusion. The enzyme activity (AST, ALT, LDH) in the perfusate were treasured to find out whether DMF causers hepatotoxicity. As perfusion continued, DMF concentration in the perfusate decreased, and NMF 1.16mM was detected. The oxygen consumption rate increased both at 10mM and 25mM DMF concentration. However, when SKF 525A, a known inhibitor of cytochrome p-450, had been pretreated (300uM before DMF addition, the oxygen consumption rate was significantly inhibited, indicating that cytochrome p-450 system is responsible for the conversion to NMF. With DMF addition, the activity of AST, ALT, and LDH significantly increased time dependently and dose dependently. However, the pretreatment of perfused liver with SKF 525A shoved that the release of AST, ALT and LDH was inhibited. In summary, it is found that DMF is metabolized to NMF in liver, and that cytochrome p-450 mono-oxygenase is suggested to play a role in the biotransformation of NMF. The time course of BMF toxicity in relation to NMF formation is compatible with hypothesis that the hepatotoxicity of DMF is mediated via NMF. Further study combined with in vivo experiment through the toxicological approaches is expected.