An ultrastructural and biochemical study of the effects of three inhibitors of cholesterol biosynthesis upon murine adrenal gland and testis. Histochemical evidence for a lysosome response.
Triparanol and 20,25-diazacholesterol inhibit cholesterol biosynthesis and result in the accumulation of desmosterol. AY-9944, another inhibitor, produces an accumulation of 7-dehydrocholesterol. Adult male C3H mice receive one of these drugs intraperitoneally. Livers, adrenal glands, and testes from each drug group are excised, and portions of each are analyzed by a modified Liebermann-Burchard reaction for quantitation of sterols. Adrenals and testes are examined also by electron microscopy. Fine-structural localization of acid phosphatase has been studied in triparanol-treated adrenal glands. Biochemical analysis reveals that 14-64% of the sterols occurs as desmosterol or 7-dehydrocholesterol. Fine-structural alterations in the adrenal glands and testes from each drug group are essentially identical. The predominant cytological feature is the occurrence of increased numbers of pleomorphic, unit-membrane-limited, electron-opaque, cytoplasmic inclusions. Hence, the cellular modifications following triparanol administration are not unique, as has been suggested. They represent a generalized phenomenon, probably related to inhibition of cholesterol biosynthesis, which is an effect common to each drug. Lead phosphate reaction product (indicating acid phosphatase activity) is demonstrable within these membrane-limited cytoplasmic bodies, identifying them as morphological lysosomes. The utilization of a lysosomal mechanism in sterol-synthesizing cells, which are accumulating cholesterol intermediates, is discussed.
D000135:Acid Phosphatase / Q000378:metabolism; D000311:Adrenal Glands / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D002784:Cholesterol / Q000096:biosynthesis; D006651:Histocytochemistry; D008099:Liver / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D013737:Testis / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D014308:Triparanol / Q000494:pharmacology*
D000924:Anticholesteremic Agents; D014308:Triparanol; D002784:Cholesterol; D000135:Acid Phosphatase