Lipid peroxidation inhibits acyl-CoA-1-acyl-sn-glycero-3-phosphocholine O-acyltransferase but not CTP:phosphocholine cytidylyltransferase activity in rat brain membranes

In brain tissue in viao peroxidized according to three model systems, we determined two microsomal enzyme activities involved in phospholipid biosynthesis. The first, short-term model. was based on the i.v, administration to normal rats, twice a day, for a period of 1 week, of a sonicated emulsion of a peroxidized mixture of phospholipids and linoleate (4:1, w/w; 500 mg/day; hydroperoxides: 200-250 nmol/mg lipid). The half-life time of the injected toxic lipid species in the blood circulation was about 1 h. At the end of the week's treatment, brain and liver malondialdehyde, conjugated diene and lipid hydroperoxide levels were significantly higher in treated rats than in the controls. The second model consisted of the acute injection of aqueous Fe2+ solution (50 mM) into lateral ventricles, and the collection of brain tissue 2 h later. The third model was based on two consecutive injections of hydroperoxylinoleate (1 mg each) into lateral ventricles over a period of 18 h, and the collection of brain tissue 2 h after the second administration. In brain microsomal membranes prepared from peroxide- or iron-treated rats; lysophosphatidylcholine acyltransferase activity exhibited a significant inhibition. On the contrary, in microsomal preparations derived from the short-term model, CTP:phosphocholine cytidylyltransferase activity was slightly stimulated. Intraventricular injection of linoleate or linoleic acid hydroperoxide left this enzyme activity unchanged. The effect of in vitro membrane peroxidation on both microsomal enzyme activities was investigated. By using an Fe2+ (20 mu M)-ascorbate (0.25 mM) peroxidation system, the residual acyltransferase and cytidylyltransferase activities were 80 and 72% of initial activity respectively. Significant dose-dependent inactivation of acyltransferase (maximum loss of 45% of initial activity) was seen when 0.1-10 mu mol of photooxidized phospholipids were preincubated with 100 mu g of microsomal membranes. Unoxidized or photooxidized phospholipids (1 mM) promoted a slight stimulation of cytidylyltransferase activity. Altogether, the results suggest a link between oxygen radical generation and the perturbation of the membrane structure in which the enzymes are located