Interactions between nutritional factors and drug biotransformations in man.

Abstract

This study was undertaken to examine the influence of nutritional factors on the activity of the mixed function oxidase system in man, which is cytochrome P450 dependent. Three normal volunteers were fed a low carbohydrate-high protein diet for 2 weeks, followed by a high carbohydrate-low protein diet for the following 2 weeks. At the end of each test diet period, the plasma elimination rates of antipyrine and theophylline were determined. The mean plasma half-life for antipyrine was 17.5 hr on the high carbohydrate-low protein diet and 9.2 hr on the low carbohydrate-high protein diet. The mean plasma half-life for theophylline was 8.9 hr on the high carbohydrate-low protein diet and 5.9 iwr on the low carbohydrate-high protein diet. These data demonstrate marked influences of dietary carbohydrate and/or protein ingestion on oxidative biotransformation of drugs in man. The effects of changes in dietary macronutrient composition on the hepatic microsomal enzymes that metabolize drugs, other foreign chemicals, and endogenous compounds, such as steroid hormones, have been studied extensively in animals (1). These studies show that dietary macronutrient composition, as well as the presence of contaminants and food additives, can influence the activities of these enzymes. Although dietary composition has been shown to be an important environmental determinant in the response of the experimental animal to pharmacological agents, such studies are lacking in man. A significant proportion of normal subjects manipulate their diets in weight-reducing regimens. Similarly, dietary treatments in clinical conditions, including obesity, atherosclerosis, and diabetes, are considered to play a significant role in the management of such disease problems. It is the purpose of these studies to show that nutritional-pharmacological interactions can occur in normal individuals when macronutrient composition of the diet is altered.In animals, in relation to hepatic microsomal enzyme activities, the dietary constituent most studied is protein. A reduction in dietary protein intake has been shown to decrease microsomal oxidations of various substrates, such as pentobarbital, aminopyrine, and zoxazolamine (2), and to increase the toxicity of foreign compounds, such as drugs (2) and pesticides (3, 4). The decreases in microsomal oxidations are accompanied by decreases in hepatic content of the hemeprotein cytochrome P-450, the terminal oxidase of the hepatic mixed function oxidase system. In contrast, the metabolism of the drugs indicated is increased in rats fed a high protein diet (2). A high carbohydrate intake has been shown to increase barbiturate-induced sleeping time in mice (5), to cause cessation of lipid peroxidase activity, and to cause a considerable decrease in liver mixed function oxidase activity in rats (6). A specific lipid role in the mixed function oxidase system was first demonstrated by Strobel et al. (7), who established the requirement for phosphatidylcholine in a reconstituted mixed function oxidase system. ...

Elevated Lipid Peroxidation in Rats Induced by Dietary Lipids and N-Nitrosodimethylamine and its Inhibition by Indomethacin Monitored Via Ethane Exhalation

“…Prooxidant states can be produced by radiation, hyperbaric oxygen, xenobiotic metabolites, Fenton-type reagents, 2). In our study, we found evidence (although indirect) that the amount of dietary lipids, known to be an enhancing factor in tumor development, can also modulate levels ofprooxidant states in the body.…”

Antipyrene clearance in Indian villagers.

“…Proof of a cause-and-effect relationship is more difficult and it is usually necessary to proceed to controlled studies in which single factors are examined in isolation, others being held constant. Alvares, Anderson, Conney & Kappas (1976) showed, using this technique, that high protein diets accelerated both antipyrine and theophylline elimination, and a similar approach will be necessary as other environmental factors, with a potential for altering drug clearance, are identified.…”

The activation of the biguanide antimalarial proguanil co‐segregates with the mephenytoin oxidation polymorphism‐a panel study.

“…Potential sources of such variability could be environmental, pathophysiological or genetic (Alvares et al, 1976;Dollery et al, 1979;Vesell, 1973). Recent interest has focussed on the genetic regulation of cytochrome P450 mixed function oxidases (Alvan et al, 1990).…”