The role of microsomal phospholipids and their fatty acid composition in the control of hepatic metabolism of lignocaine.

1 Sex differences exist in the metabolism of lignocaine by the rat liver. Microsomal phospholipids have been implicated in the control of these sex differences. Induction of diabetes in the male rat abolishes these sex differences. The difference in drug metabolism between the male and female rat is, thus, the same as that between the control and diabetic male rat. 2 By using reconstitution of delipidated male microsomal proteins with male-, female- and diabetic-derived phospholipids as well as synthetic phospholipids, it should be possible to delineate the role of phospholipids in the control of drug metabolism. 3 Female- and diabetes-derived phospholipids decrease the activity of the male-specific lignocaine N-deethylase specifically by between 35 and 52%. 4 Analysis of the phospholipid classes and fatty acid content of the various fractions indicated that stearic acid content was increased and arachidonic acid content decreased in both female- and diabetic-derived lipids as compared to control males. Linoleic acid content was decreased in female- but increased in diabetic-derived lipids as compared to control males. Subsequent correlation to N-deethylase activity, however, rules out all but the arachidonic acid content of the phospholipids as a controlling factor of lignocaine metabolism. 5 Use of synthetic phosphatidylcholine (PC) species for reconstitution indicates that diarachidonyl-PC is the most efficient at activating the N-deethylase and indicates that the degree of unsaturation of the fatty acyl side-chains of PC is of major importance in the regulation of this enzyme activity. 6 The presence of unsaturated fatty acids, and especially arachidonic acid, in the phospholipids is, thus, a major controlling influence on the specific activation of lignocaine N-deethylase in the rat liver.