Prolonged zidovudine administration induces a moderate increase in the growth and steroidogenic capacity of the rat adrenal cortex.
Zidovudine (AZT) is an antiretroviral drug widely used in the treatment of human immunodeficiency virus (HIV)-infected patients, whose prolonged administration was found to cause toxic lesions in cardiomyocytes in humans and experimental animals. Alterations in adrenocortical secretion were frequently observed in HIV patients, but it is not clear whether medication is involved in the production of these complications. Hence, we studied in vivo and in vitro, the effects of AZT on the rat adrenal cortex. The prolonged AZT administration (100 mg/kg per day for 4 months) did not cause overt qualitative morphological alterations of adrenocortical cells, which, however, underwent a net hypertrophy. Hypertrophy is associated with increases in the volume and surface area per cell of the mitochondrial compartment and smooth endoplasmic reticulum (where the enzymes of steroid synthesis are located), and a marked decrease in the volume of the lipid-droplet compartment (where cholesterol and its esters, the precursors of steroid hormones, are stored). AZT chronic treatment induced rises in the plasma concentrations of aldosterone and corticosterone, and in the basal and ACTH-stimulated in vitro secretion of these hormones from adrenal slices. The 24-h exposure to AZT (10(-5) M) did not significantly affect either secretory activity or proliferation and apoptotic rates of cultured rat adrenocortical cells. Taken together, these findings suggest that AZT chronic treatment enhances the growth and steroidogenic capacity of rat adrenal cortex, probably by activating the central branch of the hypothalamic-pituitary-adrenal axis. The toxic activity of AZT is thought to depend on increased production of ROS. On these grounds, it is likely that the lack of toxic effect of AZT on adrenocortical cells is due to their very elevated content in vitamin C, which prevents the deleterious effect of the AZT-induced increase in intracellular ROS production.
Tortorella
Cinzia
C
Department of Human Anatomy and Physiology, University of Padua, I-35121 Padua, Italy.
Guidolin
Diego
D
Petrelli
Lucia
L
De Toni
Renzo
R
Milanesi
Ornella
O
Ruga
Ezia
E
Rebuffat
Piera
P
Bova
Sergio
S
D000302:Adrenal Cortex / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism* / Q000648:ultrastructure; D000450:Aldosterone / Q000097:blood; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000494:pharmacology*; D003345:Corticosterone / Q000097:blood; D066298:In Vitro Techniques; D046529:Microscopy, Electron, Transmission; D051381:Rats; D013997:Time Factors; D015215:Zidovudine / Q000008:administration & dosage / Q000494:pharmacology*
D019380:Anti-HIV Agents; D000450:Aldosterone; D015215:Zidovudine; D003345:Corticosterone