Response of Phospholipid Metabolism to Thiram in Rat Liver Microsomes
Thiurams are potential inhibitors of hepatic mixed-function oxidases (MFO) in experimental animals and man. The underlying mechanism is largely unknown. The present investigations were designed to elucidate this inhibitory effect. Adult female Wistar rats received thiram (tetramethylthiuramdisulfide, a fungicide and rubber accelerator), 1 g/kg by stomach tube, as a suspension in gum arabic and sucrose. After 16 h the livers were subjected to extracorporeal perfusion for 1 h, the perfusate containing ca. 10 μCi u 14C glucose/100 ml. Incorporation of 14C into the phospholipid components of the liver microsomes isolated by a conventional method was determined quantitatively using β-scintillation measurement after preceding TLC separation. The percentage incorporation of 14C into respectively lysophosphatidylcholine, sphingomyelins, and phosphatidylinositol was enhanced, phosphatidylserine remaining uninfluenced. 14C incorporation into phosphatidylcholine and phosphatidylethanolamine was most strikingly depressed by about 1/3. This effect correlated strongly with an inhibition of MFO as shown by a decrease in the O-demethylation of p-nitroanisol in prepared liver microsomes. It is concluded that the reduced turnover of phosphatidylcholine, which is essential to membrane-bound electron transport, contributes to the inhibitory effect on the molecular level.