Inhibitory effects of gossypol on adrenal function

Abstract

Gossypol, an antifertility agent, has inhibitory actions on many membrane-associated enzymes, suggesting that this agent might have a generalized effect on cell membranes. This hypothesis was examined in the present study using membranes and dispersed cells prepared from human and rat adrenal glands. Four parameters were determined: microviscosity as measured by fluorescence polarization of human adrenal microsomal-and mitochondrial-enriched membranes, adrenal steroidogenic enzymes; and cAMP and cortisol responses to ACTH.It was found that gossypol increased the polarization constants of microsomes and mitochondria in a dose-dependent manner. Of the three adrenal enzymes tested, both 3\g=b\-hydroxysteroiddehydrogenase \g=D\5-\g=D\4isomerase and 11-hydroxylase were inhibited by gossypol, but not 21\ x=r eq-\ hydroxylase. Using intact human adrenocortical cells, high doses of gossypol also inhibited the ACTH-stimulated cAMP and cortisol levels. The in vivo corticosterone response to ACTH in rats subjected to chronic gossypol treatment was also found to be reduced. These findings suggest that gossypol has multiple effects on adrenal function. Its effects on membrane microviscosity, adrenal steroidogenesis, cAMP and corticosterone responses to ACTH stimulation probably occur through a generalized membrane effect.In the 1930's and 40's outbreaks of unexplained infertility were observed in several provinces of China. Entire villages went for a decade or more without a recorded birth. The agent causing the infertility was identified as gossypol, a binapthalenic component of cottonseed oil, used by citizens of these regions as cooking oil. Since that time, nu¬ merous studies have investigated the pharmaco¬ logy and toxicology of gossypol, especially as an antifertility agent in males ( 1 ). Although the mecha¬ nism of action of gossypol remains to be deter¬ mined, recent studies indicate that gossypol alters the activity of many membrane-associated enzymes including those involved in steroidogenesis (2)(3)(4)(5)(6)(7)(8). This raised the possibility that gossypol may affect adrenocortical function via a generalized action on membrane and steroidogenesis.Previous studies in our laboratory have demon¬ strated that a decrease in membrane microviscosity results in a concomitant increase in the detectable number of membrane-associated prolactin recep¬ tors (9-10). In contradistinction, an increase in membrane microviscosity induced by incorpora¬ tion of long-chain saturated fatty acids was accom¬ panied by a decrease in the responsiveness of human adrenal cells to ACTH stimulation in vitro, thus providing a possible explanation for the hypoadrenal state observed in adrenoleukodystrophy and adrenomyeloneuropathy (11). Other studies have also correlated changes in membrane micro¬ viscosity with alterations in the functionality of hor¬ mone receptors, antigenic determinants, and mem¬ brane-associated enzymes in a wide variety of cells (12). Since gossypol is known to affect many mem¬ brane-associated enzymes, a potential site of...

Gossypol Induces Death Receptor-5 through Activation of the ROS-ERK-CHOP Pathway and Sensitizes Colon Cancer Cells to TRAIL

“…In part through their ability to bind to and inactivate BH3 domain-containing anti-apoptotic proteins (20), gossypol and its analogs inhibit the growth of a wide variety of human cancer cells in culture and xenograft models (21,22).…”

Mechanism of Drug and Toxic Actions of Gossypol: Focus on Reactive Oxygen Species and Electron Transfer

“…Studies have continued into more recent times with varying results involving different types of cancer. A selection of references is presented for some of the more promising clinical and preclinical trials [41][42][43], in addition to reports on preclinical studies on mice and rats [44][45][46].…”

The biosynthesis of steroids and triterpenoids

“…549 The azasteroid 4-MA, previously described as a 5 -reductase inhibitor, has been shown to also inhibit 3 -HSD; 604 the anti-fertility agent gossypol also inhibits this enzyme. 605 Cleavage of the C-17-C-20 bond in the C 21 steroids PROG and PREG to yield the corresponding C 19 steroids A-dione and DHEA (4-ene and 5-ene pathways, respectively) is mediated by P-450 17 (P450c17; 17 -hydroxylase-17,20-lyase; 17 -hydroxylase-17,20-desmolase; P450XVII; CYP17; EC 1.14.99.9). This enzyme may also produce 17 -OH-PROG or 17 -OH-PREG as products, which then serve as substrates for biosynthesis of C 21 glucocorticoids (see later).…”