The effect of lipid composition on the metabolism of lignocaine by a reconstituted mixed function oxidase system from rat liver

Abstract Hepatic microsomal preparations from male and female rats were delipidated by column chromatography following cholate solubilisation. The enzyme activities were reconstituted using known lipids and the vesicle reconstitution method. Enzyme activity was assayed using lignocaine as the substrate for the mixed function oxidase. This substrate gives two products; one which is predominantly found in the male ( N -deethylated derivative) and one that is found in approximately equal amounts in both sexes (3-hydroxylated product). Reconstitution of male- but not female-derived enzyme in mixed dilauroylphosphatidylcholine (DLPC)/dilauroylphosphatidylethanolamine (DLPE) vesicles gave a higher N -deethylase activity than if the same enzyme was reconstituted in DLPC vesicles. 3-Hydroxylase activity, which is not sex-dependent, was not affected by DLPE. Microsomal lipids from male animals were more efficient than female-derived lipids in reconstituting N -deethylase activity from both male-and female-derived enzymes. Microsomal lipids were more efficient than DLPC in reconstituting N -deethylase activity from both male- and female-derived enzymes but 3-hydroxylase activity was similar in the two lipids. There is, thus, a sex- and pathway-dependent effect of the lipids: the male-specific N -deethylase pathway is more affected by lipid composition and then more so in the male-derived enzyme. It is possible, therefore, that some of the sex differences in drug metabolism may be related to changes in lipid composition.