The metabolism and liver toxicity of N,N-dimethylformamide in the isolated perfused rat liver.
N,N-dimethylformamide (DMF) is metabolized by the microsomal cytochrome p-450 into mainly N-hydroxymethyl- N-methylformamide (HMMF), which further breaks down to N-methyformamide (NMF). However, the detailed mechanism of its toxicity remains unclear. We investigated the metabolism and the toxicity of DMF using the isolated perfused liver model. DMF was added to the recirculating perfusate of the isolated perfused rat liver at concentrations of 0, 10 and 25 mM. Samples were collected from the inferior vena cava at 0, 30, 45, 60, 75, and 90 minutes following addition of the DMF. The metabolites of DMF were analyzed using Gas-chromatography (GC). The changes in the rate of oxygen consumption by the DMF were monitored during perfusion. The enzyme activities (aspartic aminotransferase:AST, alanine aminotransferase:ALT, and lactic dehydrogenase:LDH)) in the perfusate were monitored to see if DMF caused hepatotoxicity. As the perfusion progressed, the DMF concentration in the perfusate decreased, but the level of NMF increased to a maximum of 1.16 mM. The rate of oxygen consumption increased at DMF concentrations of 10 mM and 25 mM. However, when a known inhibitor of cytochrome p-450, SKF 525A (300 micro M), was used to pretreat the perfusate prior to the addition of the DMF, the rate of oxygen consumption was significantly inhibited, indicating the cytochrome p-450 system was responsible for the conversion of DMF to NMF. On addition of the DMF, the activities of the enzymes AST, ALT and LDH were significantly increased a time and dose dependent manner. However, following pretreatment with SKF 525A, their releases were inhibited.
Koh
Sang Baek
SB
Department of Preventive Medicine, Institute of Occupational Medicine, Wonju College of Medicine, Yonsei University, 162 Ilsan-dong, Wonju, Gangwon 220-701, Korea.
Cha
Bong Suk
BS
Park
Jong Ku
JK
Chang
Soung Hoon
SH
Chang
Sei Jin
SJ
D000818:Animals; D004126:Dimethylformamide / Q000378:metabolism* / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
D004126:Dimethylformamide