Enhancement of hepatic drug metabolism in 3-week-old pups by maternal feeding of n-3 polyunsaturated fatty acid diets

Abstract

The rates of drug oxidation and glucuronidation in the livers of 3-week-old rats that were born to and nursed by pregnant rats fed diets containing either the n-3 or the n-6 fatty acids throughout gestation and lactation were measured. Pregnant rats were fed diets containing 10% fats composed of: (1) beef tallow and corn oil (32.5% n-6 linoleic acid, control group), (2) corn oil (62.4% n-6 linoleic acid, corn oil group), (3) perilla oil (58.3% n-3 linolenic acid, perilla oil group), and (4) fish oil (35.1% n-3 eicosapentaenoic acid and 17.3% n-3 docosahexaenoic acid, fish oil group). The rates of drug oxidation (ethoxycoumarin O-deethylation) and glucuronidation (glucuronide conjugation of hydroxycoumarin), the reactions carried out by enzymes present in microsomal membranes, were determined by employing the isolated perfused liver system. While the contents of cytochromes P-450 and b 5 were not increased, the determined rates of drug oxidation were significantly higher for the pups of n-3 and n-6 fatty acid diet groups than those of the control group. The rates of both drug oxidation and glucuronidation observed for the n-3 fatty acid diet groups (perilla and fish oil) were higher than those of the n-6 fatty acid diet groups (control and corn oil). In particular, the highest rates of drug oxidation and glucuronidation were observed with the pups of fish oil diet group. The fatty acid compositions of offspring liver microsomes were influenced by the composition present in maternal diets. The n-3 and n-6 fatty acid components in maternal diet converted to their own series of longer polyunsaturated fatty acids and were substitutively incorporated into phospholipids of liver microsomal membranes in 3-week-old rats. Thus, it appeared that the hepatic microsomal drug metabolizing enzymes operated more efficiently when the proportion of n-3 polyunsaturated fatty acid in microsomal membrane phospholipid was increased. However, when the polyunsaturated/monounsaturated/saturated (P/M/S) ratios and double bond indices (an indicator of membrane fluidity) were calculated from the fatty acid composition of 3-week-old rat liver microsomes, although the P/M/S ratios maintained constant values in all groups, the double bond indices of corn, perilla, and fish oil diet groups increased in order. Furthermore, the degree of increases of double bond indices coincided with the increments of the hepatic drug oxidation rate. Therefore, it is concluded that the higher degree of unsaturation rather than the specific kinds (n-3 or n-6) of polyunsaturated fatty acids present in liver microsomal membranes is responsible for the observed increases in the rates of drug metabolism.