Inter-relationship between lipids and drug metabolism in the liver endoplasmic reticulum of rats.

Studies have been undertaken to investigate the relationship between drug-metabolizing enzyme activity and the lipid composition of rat endoplasmic reticulum, particularly in respect of the fatty acid composition of liver and of microsomal preparations as well as of the phosphatidylcholine and phosphatidylethanolamine fractions. The study comprised three aspects, as follows: 1. Effect of development. During development of rats from the foetus to adult, in both sexes, a rapid increase of drug-metabolizing enzyme activity occurs that is associated with increased synthesis of hepatic microsomal phospholipids and fatty acids. Both saturated and unsaturated fatty acids of the phospholipids increase with age in both sexes. Differences in fatty acid composition were observed between sexes at about 2-3 weeks of age. During development, a progressive decrease in the ratio of saturated to unsaturated fatty acids and an increase in the phospholipid to protein ratio occur, associated with increased membrane fluidity. 2. Effect of pregnancy and steroids. During pregnancy, a decrease in various liver microsomal enzyme activities parallels a decreased synthesis of phospholipids and fatty acids. The concentrations of phosphatidylcholine, phosphatidylethanolamine and lysophospha-tidylcholine are decreased changing the composition of the phospholipids. The fatty acid content is decreased with changes in the ratio of saturated and unsaturated fatty acids. The liver microsomal lipids returned to normal values 2-3 weeks post partum. As the inhibition of drug-metabolizing activity in pregnancy has been attributed to reduced metabolites of progesterone, non-pregnant female rats were treated with 5beta-pregnan-3alpha-ol-20-one or 16alpha-hydroxy-progesterone. Whereas treatment with pregnanolone mimics the inhibitory effects of pregnancy, 16alpha-hydroxyprogesterone enhances drug metabolism, phospholipid and fatty acid contents. 3. Effect of microsomal enzyme inducing agents. Three aspects of the induction of rat liver drug-metabolizing enzymes have been observed. (i) Phenobarbitone and Aroclor-1254 treatments increase aminopyrine N-demethylase activity, related to cytochrome P-450, whereas Aroclor-1254 and 3-methylcholanthrene treatments increase 7-ethoxy-resorufin and 7-ethoxycoumarin O-deethylase activities related to cytochrome P-448. Cytochrome P-450 reductase activity is increased by Aroclor and phenobarbitone, and is decreased by carbon tetrachloride, which also decreases gIucose-6-phosphatase and aminopyrine N-demethylase activities together with cytochrome P-450 content. (ii) Pretreatments with phenobarbitone or Aroclor-1254 result in a 50% increase in the phospholipid content of the microsomes, 3-methylcholanthrene causes no change, while carbon tetrachloride decreases the phospholipid content. (iii) Liver microsomal cholesterol content is decreased and triglycerides increased by phenobarbitone or Aroclor-1254. Sphingomyelin content is decreased by phenobarbitone, Aroclor-1254 or 3-methylcholanthrene. Carbon tetrachloride administration increases the microsomal cholesterol, triglycerides and sphingomyelin contents. The ratio of saturated to unsaturated fatty acids is decreased by phenobarbitone or Aroclor-1254, while carbon tetrachloride markedly increases this. The major effect of 3-methylcholanthrene was on the microsomal phosphatidylethanolamine fraction. All of these effects would result in changes in the fluidity of the phospholipid bilayer of the endoplasmic reticulum membrane and may thus modulate drug metabolism