Biochemical mechanism of the o,p’-DDD effect on the adrenal cortex

Abstract

o,p’-Dichlorodiphenyldichloroethane (o,p’-DDD, mitotane) is used in the treatment of adrenocortical cancer and Cushing’s disease. This medicine induces numerous biochemical changes in the adrenal cortex, as well as disorder in the mitochondrial structure. Therewith, the level of produced corticosteroid hormones is significantly reduced. One of the possible causes can be a decrease in the NADPH level due to inhibition of the activity of its reduction system and increased NADPH consumption during the glutathione reduction catalyzed by glutathione reductase. o,p’-DDD is partially metabolized in the adrenal glands, and the main metabolite (in terms of quantity) is o,p’-dichlorodiphenylacetic acid. However, attempts to find a physiologically active component among metabolites were unsuccessful. The most pronounced changes caused by o,p’-DDD were found in the mitochondria of the adrenal cortex. The respiration at the level of IV and I complexes is suppressed, the protein content of these complexes decreases. The phospholipid composition of the tissue altered and the concentration of diphosphatidylglycerol, the most important component of mitochondrial membranes, decreased. In our opinion, o,p’-DDD, owing to its high lipophilicity, accumulates in the mitochondria membranes and causes conformational disorder followed by disorder in mitochondrial functions. It was shown that o,p’-DDD acts as an inhibitor of acyl-CoA-cholesterol acyltransferase (ACAT, SOAT1). Therefore, adenocorticocytes accumulate free cholesterol, causing endoplasmic reticulum stress, mitochondrial swelling and caspases activation. Increased apoptosis leads to a decline in adrenal function and to a decrease in weight of adrenal glands.

Keywords

• adrenal cortex
• apoptosis
• chloditane
• endoplasmic reticulum stress
• glutathione
• mitochondria
• mitotane
• steroidogenesis