Inhibition of purified lysosomal phospholipase A₁ by beta-adrenoceptor blockers

Inhibition of rat liver lysosomal phospholipases is one of the main events that leads to accumulation of tissue phospholipids during drug-induced phospholipidosis. Drug inhibition of lysosomal phospholipase A may occur by direct effects of drugs on the enzyme (or substrate) or by drug-induced increases in intralysosomal pH. Although beta-adrenoceptor blockers have not been reported to cause lipid storage, they do inhibit lysosomal phospholipase A. To investigate the structural requirements for drug inhibition, we studied the effects of six beta-adrenoceptor blockers on purified rat liver lysosomal phospholipase A₁. The agents studied include: propranolol, timolol, metoprolol, practolol, atenolol and the combined alpha and beta adrenoceptor blocking agent, labetalol. The drugs varied by two logs in their abilities to inhibit phospholipase A₁ activity. The relative inhibitory potencies were propranolol > labetalol ≫ timolol > metoprolol ≫ practolol > atenolol. Our studies identify drug hydrophobicity as a key determinant for phospholipase A₁ inhibition. A strong negative correlation was noted between the octano/water partition coefficients and IC₅₀ for phospholipase inhibition (r = -0.91). The ability of propranolol to inhibit phospholipase A₁ was identical for the d, l and the d and l stereoisomers.