To study the organ-specific effect of probucol, a potent cholesterol-lowering drug, on apolipoprotein(apo)E synthesis, rabbit apoE complementary deoxyribonucleic acid (cDNA) clones were isolated and apoE messenger ribonucleic acid (mRNA) levels were determined in various tissues isolated from probucol-treated rabbits. A 0.54 kb apoE cDNA was cloned from a rabbit liver cDNA library using a synthetic oligonucleotide probe. The amino acid sequence deduced from an apoE coding region indicated 78% homology for human apoE and 63% homology for rat apoE. RNA blot analysis showed that apoE mRNA was most abundant in the liver, then in the brain and spleen. The relative amounts of apoE mRNA were determined in tissues of rabbits fed a normal diet, or high-cholesterol (1%) diet with or without probucol (1%). ApoE mRNA levels increased 2- to 4-fold in the spleen and brain after cholesterol feeding for 4 weeks and were higher by 52 to 70% in the spleen of probucol-treated rabbits than in nontreated rabbits. This induction of apoE mRNA occurs within 7 days after the initiation of probucol treatment. However, apoE mRNA levels in the liver, a major apoE-synthesizing organ, were not enhanced after probucol treatment. These results indicate that probucol induces apoE mRNA expression specifically in the spleen and may affect apoE-mediated lipoprotein metabolism, the so-called reverse cholesterol transport.