Adrenal Gland Toxicity: Chemically Induced Dysfunction

Abstract

Among the endocrine organs, the adrenal cortex appears to be the most vulnerable to chemically induced injury. A wide variety of chemicals has been found to cause morphological or functional lesions in the gland. Some of the lesions are highly localized to specific anatomical zones of the adrenal cortex, and the resulting functional deficits depend on the physiological role(s) of the zone affected. In addition, metabolic activation is an important factor contributing to the gland's vulnerability to chemical injury. For example, carbon tetrachloride (CCl4) causes adrenocortical necrosis, but only of the innermost zone of the gland, the zona reticularis. The apparent reason for the localized effect of CCl4 in the adrenal cortex is that only the cells of the zona reticularis have the enzymatic capacity to activate CCl4, resulting in lipid peroxidation and covalent binding to cellular macromolecules. By contrast, the mineralocorticoid antagonist, spironolactone, causes functional lesions in the adrenal cortex that are limited to the middle zone of the gland, the zona fasciculata. The explanation again involves metabolic activation; only the zona fasciculata converts spironolactone to a highly reactive metabolite that effects the destruction of several enzymes that are required for steroid hormone synthesis. These findings indicate that bioactivation plays a critical role in the mechanism(s) of action of various toxic agents on the adrenal cortex and also may be responsible for the anatomically localized effects of many chemicals.