Effect of Dietary Lipid on Drug-metabolizing Enzymes

Male rats fed diet containing 3% corn oil for 3 weeks metabolized hexobarbital, aniline and heptachlor significantly faster than those fed fat-free diet. Half-maximal changes in aniline hydroxylation occurred in rats fed corn oil at approximately 0.1% of calories, whereas half-maximal changes in hexobarbital oxidase and heptachlor epoxidase occurred in rats fed corn oil at 1 to 1.5% of calories. Kinetic measurements of the drug-metabolizing enzyme system in washed microsomes revealed that maximal rate of aniline and ethylmorphine metabolism in male rats occurred with 3% corn oil diet, whereas maximal rate for hexobarbital occurred with 10% corn oil diet. In female rats maximal aniline hydroxylation occurred in rats receiving 10% corn oil diet. No alterations in Km for these reactions were observed in male or female rats fed 3% corn oil but were increased in rats fed 10% corn oil for those substrates whose maximal rate of metabolism was also increased (i.e., hexobarbital in males and aniline in females). Thus qualitative changes in microsomal drug-metabolizing enzymes may occur in rats ingesting diets containing 10% corn oil. Associated with the increased drug metabolism in corn oil-fed rats were increases in concentration of cytochrome P-450 in male and female rats, decreased sleeping time in male rats, and decreased glucose 6-phosphate dehydrogenase activity of male and female rats. No change in NADPH cytochrome c reductase activity was observed. Spectral binding measurements revealed increases in substrate binding associated with increased metabolism, most of which could be ascribed to the increases in cytochrome P-450. The spectral dissociation constant for these interactions between drug and oxidized cytochrome P-450 was unaltered with the exception that it was decreased in female rats fed 10% corn oil diet. Evidence of qualitative changes in the enzymes of endoplasmic reticulum was limited to those associated with an altered fatty acid composition of phospholipid and changes in the ethylisocyanide difference spectrum of reduced microsomes.