BIOCHEMICAL-ALTERATIONS IN GUINEA-PIG ADRENAL-CORTEX FOLLOWING ADMINISTRATION OF PD-132301-2, AN INHIBITOR OF ACYL-COA-CHOLESTEROL ACYLTRANSFERASE

To assess whether previously reported ultrastructural alterations of a drenocortical mitochondria induced by the acyl-CoA:cholesterol acyltra nsferase (ACAT) inhibitor PD 132301-2 are accompanied by functional de ficits in tissue energy stores, phosphorylated adenine nucleotide leve ls in guinea pig adrenal cortex were quantitated. Adrenals of male gui nea pigs were obtained at 1, 2, 6, or 24 hours after oral administrati on of 100 mg/kg PD 132301-2 or 0.5 % methylcellulose vehicle. In treat ed animals, ATP levels and ATP/ADP ratios were decreased approximately 50 % with concurrent increases in AMP. Calculated energy charge was a lso decreased; these decreases were maximal by 6 hours. Cholesterol es terification in adrenal cortex was inhibited, resulting in progressive accumulation of free cholesterol up to 3-fold over control by 24 hour s, consistent with the ACAT inhibitory activity of the drug. These dat a suggest that PD 132301-2 distributes to the adrenal cortex where ear ly alterations of tissue bioenergetics occur in a time frame consisten t with ultrastructural alterations of mitochondria.