Uniquely equipped for cholesterol synthesis and using cholesterol in steroid hormone synthesis, the adrenal cortex can also metabolize steroids to less active forms. We investigate the differential regulation of these functions whose sum determines the amount of active hormone leaving the adrenal. Seeking underlying mechanisms, we use combined biochemical, immunochemical, and molecular biological techniques on well-defined, hormonally modulatable in vitro and in vivo cell systems.

We focus on cytochrome P450s (CYPs), a large gene superfamily whose members participate in oxidative metabolism of both endogenous and exogenous compounds. In the adrenal, several superfamily members act as steroid hydroxylases to produce the major active adrenocorticosteroids: aldosterone, corticosterone, and cortisol. Differential regulation of CYP17 and CYP11B is pivotal in determining which products are synthesized by each zonal cell type, i.e., products involved in regulating salt and water balance, body metabolism, reproductive function, and immune and stress responses.

Adrenals also possess CYPs that can further metabolize these important corticosteroids. Suppression by ACTH and male-predominance suggests a sex-differentiated role for these CYPs in the regulation of steroid output by the adrenal. Their dual capacity for metabolism of foreign compounds implies that induction by drugs, aromatic hydrocarbons, and other xenobiotics could alter the spectrum of steroids leaving the adrenal. cDNA and gene availability for these proteins will allow us to analyze the molecular mechanisms regulating these unique adrenal CYPs. Our ultimate goal is to illucidate ways in which environmental agents and drugs may alter endocrine balance, resulting in dysfunction and disease.