Tunicamycin caused marked decreases in liver cytochrome P-450 levels in a dose-dependent fashion but only a small effect (15% at 50 Mug/kg) decreased in cytochrome c reductase activity 50 Mug/kg decreased cytochrome P-450 by 50%. Whereas 100 Mum/kg tunicamycin decreases by 80%. Since higher doses caused more than 50% mortality, 50 Mug/kg dose was used for all experiments. The reduction of cytochrome P-450 was much more marked with control animals than phenobarbital-induced animals. Tunicamycin did not lower cytochrome P-450 within 24 hrs and required three daily doses to cause a decrease in cytochrome P-450. Since tunicamycin caused a marked decrease in food and water intake, the effect of tunicamycin was examined in animals which were either deprived of food and water or food alone. The effect of food and water deprivation on cytochrome P-450 was minimal and tunicamycin still caused a marked reduction in the cytochrome P-450 in these animals indicating the loss of cytochrome P-450 by tunicamycin was not due to suppression of food and water intake. The effect of tunicamycin on the glycosylation of cytochrome P-450 is being examined. Electrophoresis of microsomal protein of tunicamycin treated rats indicated a general loss of cytochrome P-450 apoprotein in the microsomes with a concomitant loss of the cytochrome P-450 levels. Antibody staining of the gels after Western blotting also indicated a great loss of apoproteins. The mechanism by which tunicamycin induced a specific loss of cytochrome P-450 remains obscure.