Abstract
The effects of age and different diets on the activity of hepatic drug-metabolizing enzymes have been studied in rats. The enzymes studied were biphenyl 2- and 4-hydroxylase, p-nitrobenzoate reductase, 4-methyl-umbelliferone glucuronyltransferase, and cytochrome P-450 which is regarded as the major terminal mixed-function oxidase in hepatic microsomal hydroxylations. The activity of these enzymes was determined at various ages between 6 and 100 days postnatum. The activity of each enzyme rose to a peak at a different rate. The peak was reached soon after weaning, and activity then decreased with age to the mature level. With biphenyl 2-hydroxylase, the activity fell rapidly after 31 days and disappeared altogether at 70 days. During the first three weeks of postnatal life, undernutrition did not result in any significant change in the activity per g. liver weight of the enzymes studied. The total activity of the enzymes per liver was, however, lower, in the livers of the undernourished animals due to the smaller size of the liver. In male weanling rats pair fed with respect to proteins with additional calories fed for 7, 14 and 28 days, the hepatic concentration of the enzymes was, in general increased. The activity of glucuronyl transferase was, however, depressed in the absence of additional calories and cytochrome P-450 was depressed in the presence of additional calories. In the animals fed the protein deficient diet with additional calories, the rise in the activity of biphenyl 4-hydroxylase was sufficient to compensate for the lower liver weight so that the absolute amount per liver was the same as in the controls. The adaptive response of this enzyme to the protein deficient diet in the in vitro studies was further suggested by the finding that the capacity of the body to metabolize biphenyl and excrete it as hydroxy-biphenyl in the urine was similar to that of control animals. Any possibility of a conformational change of the enzyme site being responsible for the adaptive response of the enzyme has been excluded. However, a correlation between the increase of biphenyl 4-hydroxylase activity and plasma corticosteroid level in protein deficient animals has been observed. The possibility of the adaptive response being mediated by corticosteroids has further been supported by the increase in the concentration of biphenyl 4-hydroxylase as a result of corticosterone administration in well-fed animals. The current investigation has been extended by a study of the effect of substitution of starch by sucrose, glucose, fructose or an equimolar mixture of glucose and fructose on the activity of drug-metabolizing enzymes in growing rats. The presence of sucrose in the diet at concentrations of either 60% or 10% depressed activity of biphenyl 2- and 4-hydroxylases and level of cytochrome P-450. Other disaccharides, such as lactose or maltose did not have the same effect.